Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient

ABSTRACT

Pharmaceutical composition containing aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (1) and the salts thereof as active ingredient (wherein R 1  is H, alkyl; R 2  is COOR 7 , CONHOR 8 ; E is —CONR 9 —, —NR 9 CO—, —OCO—,—COO—, —CH 2 —O—, —(CH 2 ) 2 —, vinylene, ethynylene; J is bond, alkylene; A is H, alkyl, Ar, alkyl-OH ; R 3 , R 4  is H, alkyl, COOR 19 , hydroxy, —NR 20 R 21 ,                    
     Ar 1  etc.); R 5 , R 6  is H, methyl) and the novel aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (I).                    
     The compounds of the formula (I) have inhibitory activity against matrix metalloproteinases, therefore, the compounds of the formula (I) are useful for prevention and/or treatment of rheumatoid diseases, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, autoimmune diseases, diseases caused by vascular emigration or infiltration of leukocytes, arterialization etc.

This application is a 371 of PCT/JP97/02200 filed Jun. 25, 1997.

FIELD OF THE INVENTION

This invention relates to aryl (sulfide, sulfoxide, sulfone)derivatives, processes for the preparation thereof, and matrixmetalloproteinases inhibitors containing them as active ingredient.

More particularly, this invention relates to matrix metalloproteinasesinhibitors containing aryl (sulfide, sulfoxide, sulfone) derivatives ofthe formula (I)

(wherein all the symbols are the same meanings as hereinafterdescribed.), non-toxic salts thereof, as active ingredient, and theabove-mentioned novel aryl (sulfide, sulfoxide, sulfone) derivatives ofthe formula (I), non-toxic salts thereof, and processes for thepreparation thereof.

BACKGROUND OF THE INVENTION

The matrix metalloproteinases (hereinafter abbreviated as MMP) areneutral metalloproteinases and zinc (hereinafter abbreviated as Zn²⁺) isessential in the active site for their activation They degrade collagen,laminin, proteoglycans, fibronectin, elastin, gelatin etc. underphysiological conditions and, therefore, are effective on growth andtissue remodeling of articulation tissue, bone tissue and connectivetissue. At least 10 classes of MMP which differ in primary structure areidentified.

As common characteristics of these enzymes, MMP

(1) have Zn²⁺ in the active site and the activity depends on calcium(Ca²⁺),

(2) are secreted as an inactive proenzyme and activated outside ofcells,

(3) have high homology on amino acid sequence,

(4) have an ability to degrade various extracellular matrix componentsin vivo,

(5) are regulated by tissue inhibitors of metalloproteinases (TIMP)which are specific to MMP.

MMP inhibitors are useful for prevention and/or treatment of variousdiseases induced by overexpression or excess activation of MMP. Suchdiseases are, for example, rheumatoid diseases, arthrosteitis, unusualbone resorption, osteoporosis, periodontitis, interstitial nephritis,arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury,metastasis of, invasion of or growth of tumor cells, autoimmune diseases(e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascularemigration or infiltration of leukocytes, arterialization etc.

Some compounds possessing inhibitory activity against matrixmetalloproteinases are known. A sequence in the vicinity of the cleavagesite of collagen (Gly-Ile-Ala-Gly or Gly-Leu-Ala-Gly) has high affinityfor collagenase. Much research and development on substrate analogousmatrix metalloproteinases inhibitors, which are chemically modified soas to have zinc affinity groups on a cleavage site of the substrate, hasenergetically been carried out [Inhibitors of matrix metalloproteinases(MMP's), Nigel RA Beeley, Phillip R J Ansell, Andrew J P Docherty etal., Curr. Opin. Ther. Patents, 4, 7-16 (1994), Current Drugs Ltd ISSN0962-2594]. However, these substrate-analogous inhibitors might havevarious problems. Therefore, it is desired to obtain a non-peptideinhibitor and some compounds are reported.

For example, (1) in the specification of EP 606046, arylsulfonamidederivatives of the formula (X)

(wherein (a) Ar^(X) is carbocyclic or heterocyclic aryl; R^(X) ishydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R^(1X) ishydrogen, lower alkyl, carbocyclic aryl-lower alkyl etc.; R^(2X) ishydrogen, lower alkyl; or (b) R^(X) and R^(1X) taken together with thechain to which they are attached form 1,2,3,4-tetrahydro-isoquinoline,piperidine etc.; Ar^(X) and R^(2X) are as defined in (a); or (c) R^(1X)and R^(2X) taken together with the carbon to which they are attachedform C3-7 cycloalkane, oxa-cyclohexane, thia-cyclohexane etc. which isunsubstituted or substituted by lower alkyl; and Ar^(X) and R^(2X) areas defined in (a).) are disclosed to have inhibitory activity againstmatrix metalloproteinase.

(2) In the specification of WO 9535276, the compounds of the formula (Y)

(wherein X^(Y) is COOH, CONHOH; R^(1Y) is α-amino acid; R^(2Y) isZ^(1Y)Q^(Y)W^(Y); Z^(1Y) is hydrogen, aryl etc.; (i) Q^(Y)W^(Y) togetherform bond, (ii) Q^(Y) is O, S, W^(Y) is C1-20 alkyl etc., (iii) Q^(Y) isbond, W^(Y) is C9-20 alkyl etc., (iv) Q^(Y) is bond, W^(Y) is C1-8alkyl; Y^(Y) is SO₂; Z^(Y) is aryl, heteroaryl.)

are disclosed to have inhibitory activity against matrixmetalloproteinase.

(3) In the specification of WO 9615096, the compounds of the formula (Z)

(T^(Z))x^(Z)A^(Z)-B^(Z)-D^(Z)E^(Z)G^(Z)  (Z)

(wherein (T^(Z))x^(Z)A^(Z) is unsubstituted or substituted variousaromatic ring or aromatic hetero ring; B^(Z) is various aromatic ring oraromatic hetero ring; D^(Z) is —CO—, —CH(OH)—, —CH₂— etc.; E^(Z) is Cncarbon chain optionally having R^(6Z) (in which R^(6Z) is—(CH₂)v^(Z)Z^(Z)R^(8Z) (in which v^(Z) is 0, integer of 1≠4; Z^(Z) is—S—, —SO—, —SO₂— etc.; R^(8Z) is optionally substituted C6-10 aryletc.)); G^(Z) is carboxyl, alkoxycarbonyl.)

are disclosed to have inhibitory activity against matrixmetalloproteinase.

(4) In the specification of WO 9509841, the compounds of the formula (E)

(wherein R^(1E) is phenyl optionally having substituent etc.; R^(2E) ishydrogen, C1-6 alkyl etc.; R^(3E) is amino acid residue optionallyhaving substituent; R^(4E) is hydrogen, C1-6 alkyl etc.; R^(5E) ishydrogen, methyl; n^(E) is 0, 1, 2; A^(E) is C1-6 hydrocarbon chain.)

are disclosed to have inhibitory activity against the liberation of TNF,and inhibitory activity against matrix metalloproteinase.

(5) In the specification of WO 9324449, the compounds of the formula (F)

(wherein RF is —CONHOH, carboxyl, esterified carboxyl etc.; R^(1F) ishydrogen, optionally substituted alkyl, alkenyl, aryl, aralky,heteroaralkyl, heteroarylthioalkyl; R^(2F) is optionally substitutedarylthio, arylthioalkyl etc.; R^(3F) is hydrogen, alkyl; R^(4F) ishydrogen, alkyl; R^(5F) is optionally substituted alkyl etc.) aredisclosed to have inhibitory activity against matrix metalloproteinase.

(6) In the specification of WO 9616027, the compounds of the formula (G)

(wherein R^(1G) is —CONHOH, carboxyl, alkoxycarbonyl, aryloxycarbonyl,benzyloxycarbonyl etc.; R^(2G) is aryl etc.; R^(3G) is alkyl etc.;R^(7G) is aryl etc.; X^(G) is —(CH₂)m^(G)Y^(G)(CH₂)n^(G) (in which Y^(G)is S etc.; m^(G), n^(G), p^(G) is 0˜4.)

are disclosed to have inhibitory activity against matrixmetalloproteinase.

Also, (7) in the specification of Japanese Patent Kokai No. 4-226939 and(8) Japanese Patent Kokai No. 4-293576, each of the compound of theformula (W-1)

(wherein R^(1W-1), R^(2W-1) is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, ortogether form methylene, ethylene, polymethylene; R^(3W-1) is hydrogen,halogen, haloalkyl, C1-12 alkyl, C1-12 alkoxy etc.; R^(4W-1) ishydrogen, halogen, nitro, —C(O)CH₃, S(O)_(p)R^(9W-1) (in which p is 0,1, 2, R^(9w-1) is hydroxy, —ONa, optionally substituted C1-12 alkyl,cycloalkyl)),

and the compounds of the formula (W-2)

(wherein R^(1W-2), R^(2W-2) is hydrogen, C1-4 alkyl, C3-6 cycloalkyl, ortogether form methylene, ethylene, polymethylene; Ar^(W-2) is optionallysubstituted phenyl; HET^(W-2) is hetero ring containing nitrogen, sulfuror oxygen atom over 1 atom.) are disclosed to have inhibitory activityagainst elastase.

(9) In the specification of EP 0173516, the compounds of the formula (J)

(wherein B^(J) is —SCH₂— etc.; T^(J) is oxygen etc.; R^(1J) isoptionally substituted phenyl, naphthyl by R^(5J), R^(6J), or C1-20alkyl, alkenyl, alkynyl; R^(2J) is hydrogen, C1-6 alkyl; R^(3J) ishydrogen, alkyl etc.; R^(4J) is —(CH₂)p^(J)—COOR^(8J) (in which p^(J) is0˜10; R^(8J) is hydrogen, C1-6 alkyl.)

are disclosed to have SRS antagonistic activity or 5a-reductaseinhibitory activity.

(10) In the specification of British Patent 2031408, the compounds ofthe formula (K)

(wherein R^(K) is hydrogen, alkyl; A^(1K), A^(2K) is alkylene,alkenylene; m^(K) is 0, 1; Z^(K) is

etc.; R^(1K), R^(2K) is hydrogen, alkyl.)

are disclosed to have inhibitory activity against TXA₂ synthetase.

(11) In the specification of British Patent 2039903, the compounds ofthe formula (L)

(wherein A^(L) is C1-5 alkylene optionally substituted by hydroxy; E^(L)is

etc.; B^(L) is sulfur etc.; Z^(L) is bond, C≡C,

D^(L) is bond, C1-5 alkylene; R^(1L) is COOR^(4L) etc.; R^(4L) ishydrogen, C1-12 alkyl etc.)

are disclosed to have inhibitory activity against TXA₂ synthetase.

(12) In the specification of U.S. Pat. No. 4,461,905, the compounds ofthe formula (M)

(wherein A^(M), B^(M) is C1-8 alkylene, alkenylene; D^(M) is C2-10 acyl,C2-7 alkoxycarbonyl etc.; Q^(M) is C2-7 alkoxycarbonyl etc.; X^(M) ishalogen; n^(M) is 0, 1; Z^(M) is

;EM is hydrogen, C1-6 alkyl etc.; Y^(M) is sulfur etc.)

are disclosed to have inhibitory activity against TXA₂ synthetase.

(13) In the specification of WO 865779, the compounds of the formula (N)

(wherein X^(1N) is —CH₂CH₂—, —CH═CH—, —CH₂—Y^(1N)—, —Y^(1N)—CH₂—,—COY^(2N)—, —Y^(2N)—CO— (in which Y^(1N) is oxygen etc.; Y^(2N) is —NH—,—CH₂Y^(1N), —Y^(1N)CH₂—);

is phenylene etc.; X^(2N) is Y^(3N)—Y^(4N)— (in which Y^(3N) is sulfuretc.; Y^(4N) is C1-6 alkylene); D^(N) is —COOH, lower alkoxycarbonyletc.; R^(1N) is hydrogen, lower alkyl; n^(N) is 3˜10; A^(N) is hydrogen,phenyl, phenoxy.)

are disclosed to have SRS antagonistic activity.

(14) in the specification of EP 181568, the compounds of the formula (P)

Ar₁ ^(P)—X^(P)—Ar^(p)—z^(P)—(R^(P))n^(P)  (P)

(wherein Ar^(P) is phenyl etc.; Z^(P) is C1-10 alkylene optionallycontaining 0˜2 double bonds, and it may be attached to Ar^(P) throughsulfur etc.; R^(P) is carboxy, alkoxycarbonyl etc.; n^(P) is 0, 1; X^(P)is —CH═CH—, ethynylene, —COO—, —CONR^(1P)— etc.; Ar₁ ^(P) is phenyl,hetero ring containing N, S, O atom.) are disclosed to have5-lipoxygenase inhibitory activity.

Also, the following compounds are already known. However, it is notdisclosed that each compounds have inhibitory activity against matrixmetalloproteinases, and it is not disclosed to suggest that thesecompounds have the activity thereof (the figure in the parenthesesrepresents Chemical Abstract number.).

(1) 3-(4-methylphenylsulfonyl)propionic acid isopropyl ester(122-323393),

(2) 3-(4-methylphenylsulfonyl)propionic acid phenyl ester (095-006058),

(3) 3-(4-methylphenylsulfonyl)propionic acid sodium salt (094-174529),

(4) 3-(4-methylphenylsulfonyl)propionic acid methyl ester (122-323393),

(5) 3-(4-methylphenylsulfonyl)propionic acid ethyl ester (122-323393),

(6) 3-(4-methylphenylsulfonyl)propionic acid (121-009456),

(7) 3-(4-ethylphenylsulfonyl)propionic acid (100-200853),

(8) 3-(4-methoxyphenylsulfonyl)propionic acid phenyl ester (095-006058),

(9) 3-(4-methoxyphenylsulfonyl)propionic acid,

(10) 3-(4-nitrophenylsulfonyl)propionic acid methyl ester (122-323393),

(11) 3-(4-nitrophenylsulfonyl)propionic acid isopropyl ester(122-323393),

(12) 3-(4-nitrophenylsulfonyl)propionic acid,

(13) 3-(4-aminophenylsulfonyl)propionic acid ethyl ester (115-072840),

(14) 3-(4-aminophenylsulfonyl)propionic acid (085-048254),

(15) 3-(4-hydroxyphenylsulfonyl)propionic acid,

(16) 3-(4-hydroxyphenylsulfonyl)propionic acid phenyl ester(111-164337),

(17) 3-(4-bromophenylsulfonyl)propionic acid methyl ester (066-104778),

(18) 3-(4-bromophenylsulfonyl)propionic acid ethyl ester (066-104778),

(19) 3-(4-bromophenylsulfonyl)propionic acid phenyl ester (095-006058),

(20) 3-(4-chlorophenylsulfonyl)propionic acid methyl ester (066-104778),

(21) 3-(4-chlorophenylsulfonyl)propionic acid ethyl ester (066-104778),

(22) 3-(4-chlorophenylsulfonyl)propionic acid t-butyl ester(122-323393),

(23) 3-(4-chlorophenylsulfonyl)propionic acid isopropyl ester (122-323393),

(24) 3-(4-chlorophenylsulfonyl)propionic acid (101-006755),

(25) 3-(4-chlorophenylsulfonyl)propionic acid phenyl ester (095-006058),

(26) 3-(4-iodophenylsulfonyl)propionic acid ethyl ester (066-104778),

(27) 3-(4-iodophenylsulfonyl)propionic acid methyl ester (066-104778),

(28) 3-(4-acetylaminophenylsulfonyl)propionic acid methyl ester(114-014686),

(29) 3-(4-acetylaminophenylsulfonyl)propionic acid ethyl ester(115-072840),

(30) 3-(4-vinylphenylsulfonyl)propionic acid sodium salt (094-174529),

(31) 3-(4-carboxyphenylsulfonyl)propionic acid,

(32) 3-(4-cyanophenylsulfonyl)propionic acid ethyl ester,

(33) 3-(4-formylphenylsulfonyl)propionic acid ethyl ester,

(34) 3-(4-biphenylsulfonyl)propionic acid methyl ester (093-061046),

(35) 2-amino-3-(2-methylphenylsulfonyl)propionic acid (53-14959g),

(36) 2-amino-3-(3-methylphenylsulfonyl)propionic acid (53-149599),

(37) 2-amino-3-(4-methylphenylsulfonyl)propionic acid (53-14959g),

(38) 2-amino-3-(4-fluorophenylsulfonyl)propionic acid (53-14959g),

(39) 2-t-butoxycarbonylamino-3-(4-fluorophenylsulfonyl)propionic acid(124-289512),

(40) 2-amino-3-(4-chlorophenylsulfonyl)propionic acid (53-14959g),

(41) 2-t-butoxycarbonylamino-3-(4-chlorophenylsulfonyl)propionic acid(124-117961),

(42) 2-amino-3-(3-trifluoromethylphenylsulfonyl)propionic acid(53-14959h),

(43) 2-amino-3-(4-nitrophenylsulfonyl)propionic acid (119-95106),

(44) 2-amino-3-(2-nitrophenylsulfonyl)propionic acid (119-95106),

(45) 2-amino-3-(4-aminophenylsulfonyl)propionic acid (119-95106),

(46) 2-amino-3-(2-aminophenylsulfonyl)propionic acid (119-95106),

(47) 2,2-dimethyl-3-(4-hydroxyphenylthio)propionic acid ,

(48) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-phenylbutylate,

(49) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-phenylbutylate,

(50) 4-(2-carboxy-2-methylpropylsulfonyl)phenyl 2-phenylbutylate,

(51) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(4-methoxyphenyl)isobutylate,

(52) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(3,4-diethylphenyl)isobutyric acid,

(53) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(1,2,3,4-tetrahydro-6-naphthyl)butyrate,

(54) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(1-methyl-2-pyrrole)butyrate,

(55) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl2-(1-methyl-2-pyrrole)butyrate,

(56) 3-(4-bromophenylthio)propionic acid,

(57) N-t-butoxy-3-(4-bromophenylthio)propionamide,

(58) N-t-butoxy-3-(4-biphenylthio)propionamide

Compound (47)˜(49) and Compound (50)˜(55), respectively, are describedin the above-mentioned (7) Japanese Patent Kokai 4-226939 and (8)Japanese Patent Kokai 4-283576.

DISCLOSURE OF THE INVENTION

Energetic investigations have been carried out in order to make a matrixmetalloproteinase inhibitor. As a result, the present inventors havefound that the purpose may be achieved with aryl (sulfide, sulfoxide,sulfone) derivatives of the formula (I).

Most of aryl (sulfide, sulfoxide, sulfone) derivatives of the formula(l) are not known and are novel compounds.

Further, the present inventors have also found that the compounds of thepresent invention may have a particularly inhibitory activity againstmatrix metalloproteinases, especially, class of gelatinases.

The present invention relates to

1) matrix metalloproteinases inhibitors containing aryl (sulfide,sulfoxide, sulfone) of the formula (I)

(wherein

R¹ is hydrogen, or C1-4 alkyl,

R² is —COOR⁷ or —CONHOR⁸,

R⁷ is hydrogen, C1-8 alkyl, phenyl, or

C1-4 alkyl substituted by phenyl, —OCOR²³ (in which R²³ is C1-4 alkyl.),or —CONR²⁴R²⁵ (in which R²⁴ and R²⁵, each independently, is hydrogen orC1-4 alkyl.),

R⁸ is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,

E is —CONR⁹—, —NR⁹CO—, —OCO—, —COO—, —CH₂—O—, —CO—CH₂—, —(CH₂)₂—,—CH═CH— or —C≡C— (in which R⁹ is hydrogen, C1-4 alkyl, phenyl, or C1-4alkyl substituted by phenyl. With proviso that left side of each groupsis attached to J group.),

J is bond or C1-8 alkylene,

A is

1) hydrogen,

2) C1-8 alkyl,

3) Ar group (Ar group is carbocyclic ring or heterocyclic ringoptionally substituted by 1˜3 of

i) C1-15 alkyl,

ii) C1-15 alkoxy,

iii) halogen,

iv) nitro,

v) cyano,

vi) guanidino,

vii) amidino,

viii) hydroxy,

ix) benzyloxy,

x) NR¹²R¹³ (in which R¹² and R¹³, each independently, is hydrogen, C1-4alkyl or —COOR¹⁴ (in which R¹⁴ is C1-4 alkyl or benzyloxy.).),

xi) —COOR¹⁵ (in which R¹⁵ is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkylsubstituted by phenyl.),

xii) trilluoromethyl,

xiii) carbocyclic ring,

xiv) heterocyclic ring or

xv) C1-4 alkyl substituted by hydroxy, C1-4 alkoxy, NR¹²R¹³ (in which

R¹² and R¹³ are the same meanings as hereinbefore described.), —COOR¹⁵(in which R¹⁵ is the same meaning as hereinbefore described.),carbocyclic ring or heterocyclic ring.) or

4) C1-4 alkyl substituted by hydroxy or C1-4 alkoxy, or

A, J and E taken together, represents methyl, halogen, trifluoromethyl,nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (in which R¹⁶ and R¹⁷,each independently, is hydrogen, C1-4 alkyl, —COOR¹⁸ (in which R¹⁸ isC1-4 alkyl or benzyl.).), or heterocyclic ring (this heterocyclic ringmay be optionally substituted by 1˜4 of C1-4 alkyl, C1-4 alkoxy,halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro,NR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings as hereinbeforedescribed.) or CONR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings ashereinbefore described.).),

R³and R⁴, each independently, is

(1) hydrogen,

(2) C1-8 alkyl (with proviso that one of the carbon atom in C1-8 alkylmay be replaced by a sulfur atom.),

(3) —COOR¹⁹ (in which R¹⁹ is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkylsubstituted by phenyl.),

(4) Ar₁ group (Ar₁ group is carbocyclic ring or heterocyclic ringoptionally substituted by 1˜3 of C1-4 alkyl, C1-4 alkoxy, halogen,hydroxy or trifluoromethyl.),

(5) hydroxy,

(6) —NR²⁰R²¹ (in which R²⁰ and R²¹, each independently, is hydrogen,C1-4 alkyl, —COOR²² or —COR²² (in which R²² is C1-4 alkyl or benzyl.),

(7)

(in which R^(a) is hydrogen or phenyl, R^(b) is hydrogen, —COOR²² or—COR²² (in which R²² is the same meaning as hereinbefore described.), pis 1 or 2.), or

(8) C1-8 alkyl substituted by substituent selected from the following(a)˜(f) (with proviso that one of the carbon atom in C1-8 alkyl may bereplaced by a sulfur atom.);

(a) —COOR¹⁹ (in which R¹⁹ is the same meaning as hereinbeforedescribed.)

(b) C1-4 alkoxy,

(c) hydroxy,

(d) benzyloxy,

(e) —NR²⁰R²¹ (in which R²⁰ and R²¹ are the same meanings as hereinbeforedescribed.), or

(f) Ar₁ group (in which Ar₁ is the same meaning as hereinbeforedescribed.)

or R³ and R⁴ taken together with the carbon to which they are attached,form C3-7 cycloalkyl,

R⁵ and R⁶ is hydrogen or methyl, or R³ and R⁵ taken together, form bond,R⁴ and R⁶ are the same meanings as hereinbefore described,

n is 0, 1 or 2.

With proviso that:

when A, J and E taken together, form phenyl, and R² is CONHOH, then n is1 or 2.)

or non-toxic salts thereof, as active ingredient,

2) aryl (sulfide, sulfoxide, sulfone) derivatives of the formula (I)

(wherein

R¹ is hydrogen, or C1-4 alkyl,

R² is —COOR⁷ or —CONHOR⁸,

R⁷is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,—OCOR²³ (in which R²³ is C1-4 alkyl.), or —CONR² R²⁵ (in which R²⁴ andR²⁵ each independently, is hydrogen or C1-4 alkyl.),

R⁸ is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,

E is —CONR⁹—, —NR⁹CO—, —OCO—, —COO, —CH₂—O—, CO—CH₂—, —(CH₂)₂—, —CH═CH—or —C═C— (in which R⁹ is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkylsubstituted by phenyl. With proviso that left side of each groups isattached to J group.), J is bond or C1-8 alkylene,

A is

1) hydrogen,

2) C1-8 alkyl,

3) Ar group (Ar group is carbocyclic ring or heterocyclic ringoptionally substituted by 1˜3 of

i) C1-1 5 alkyl,

ii) C1-15 alkoxy,

iii) halogen,

iv) nitro,

v) cyano,

vi) guanidino,

vii) amidino,

viii) hydroxy,

ix) benzyloxy,

x) NR¹²R¹³ (in which R¹² and R¹³, each independently, is hydrogen, C1-4alkyl or —COOR¹⁴ (in which R¹⁴ is C1-4 alkyl or benzyloxy.).),

xi) —COOR¹⁵ (in which R¹⁵ is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkylsubstituted by phenyl.),

xii) trifluoromethyl,

xiii) carbocyclic ring,

xiv) heterocyclic ring or

xv) C1-4 alkyl substituted by hydroxy, C1-4 alkoxy, NR¹²R¹³ (in whichR¹² and R¹³ are the same meanings as hereinbefore described.), —COOR¹⁵(in which R¹⁵ is the same meaning as hereinbefore described.),carbocyclic ring or heterocyclic ring.) or

4) C1-4 alkyl substituted by hydroxy or C1-4 alkoxy, or

A, J and E taken together, represents methyl, halogen, trifluoromethyl,nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (in which R¹⁸ and R¹⁷,each independently, is hydrogen, C1-4 alkyl, —COOR¹⁸ (in which R¹⁸ isC1-4 alkyl or benzyl.).), or heterocyclic ring (this heterocyclic ringmay be optionally substituted by 1˜4 of C1-4 alkyl, C1-4 alkoxy,halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro,NR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings as hereinbeforedescribed.) or CONR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings ashereinbefore described.).),

R³ and R⁴, each independently, is

(1) hydrogen,

(2) C1-8 alkyl (with proviso that one of the carbon atom in C1-8 alkylmay be replaced by a sulfur atom.),

(3) —COOR¹⁹ (in which R¹⁹ is hydrogen, C1-8 alkyl, phenyl, or C1-4 alkylsubstituted by phenyl.),

(4) Ar₁ group (Ar₁ group is carbocyclic ring or heterocyclic ringoptionally substituted by 1˜3 of C1-4 alkyl, C1-4 alkoxy, halogen,hydroxy or trifluoromethyl.),

(5) hydroxy,

(6) —NR²⁰R²¹ (in which R²⁰ and R²¹, each independently, is hydrogen,C1-4 alkyl, —COOR²² or —COR²² (in which R²² is C1-4 alkyl or benzyl.),

(7)

(in which R^(a) is hydrogen or phenyl, R^(b) is hydrogen, —COOR²² or—COR²² (in which R²² is the same meaning as hereinbefore described.), pis 1 or 2.), or (8) C1-8 alkyl substituted by substituent selected fromthe following (a)˜(f) (with proviso that one of the carbon atom in C1-8alkyl may be replaced by a sulfur atom.);

(a) —COOR¹⁹ (in which R¹⁹ is the same meaning as hereinbeforedescribed.)

(b) C1-4 alkoxy,

(c) hydroxy,

(d) benzyloxy,

(e) —NR²⁰R²¹ (in which R²⁰ and R²¹ are the same meanings as hereinbeforedescribed.), or

(f) Ar₁ group (in which Ar₁ is the same meaning as hereinbeforedescribed.)

or R³ and R⁴ taken together with the carbon to which they are attached,form C3-7 cycloalkyl,

R⁵ and R⁶ is hydrogen or methyl, or R³ and R⁵ taken together, form bond,R⁴ and R⁶ are the same meanings as hereinbefore described,

n is 0, 1 or 2.

With proviso that:

(a) when A, J and E taken together, form phenyl, and R² is CONHOH, thenn is 1 or 2.

(b) when R² is —COOR⁷, R⁷ is hydrogen, C1-8 alkyl, phenyl or C1-4 alkylsubstituted by phenyl, then A, J and E taken together, do not representmethyl, halogen, trifluoromethyl, nitro, cyano, hydroxy, NR¹⁶R¹⁷ (inwhich R¹⁶ and R¹⁷, each independently, is hydrogen.)

(c) when R² is —COOR⁷, R⁷ is hydrogen, C1-8 alkyl, phenyl or C14 alkylsubstituted by phenyl, A is hydrogen or C1-8 alkyl, J is bond or C1-8alkyl, then E do not represent —CH₂—O—or —CH₂)₂O—.

(d) the following (1)˜(16) compounds are excluded.

(1) 3-(4-acetylaminophenylsulfonyl)propionic acid methyl ester,

(2) 3-(4-acetylaminophenylsulfonyl)propionic acid ethyl ester,

(3) 3-(4-vinylphenylsulfonyl)propionic acid sodium salt,

(4) 3-(4-carboxyphenylsulfonyl)propionic acid,

(5) 3-(4-formylphenylsulfonyl)propionic acid ethyl ester,

(6) 3-(4-biphenylsulfonyl)propionic acid methyl ester,

(7) 4-(2-carboxy-2-methylpropylmercapto)phenyl 2-phenylbutylate,

(8) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-phenylbutylate,

(9) 4-(2-carboxy-2-methylpropylsulfonyl)phenyl 2-phenylbutylate,

(10) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(4methoxyphenyl)isobutylate,

(11) 4-(2-carboxy-2methylpropylmercapto)phenyl2-(3,4-diethylphenyl)isobutylate,

(12) 4-(2-carboxy-2-methylpropylmercapto)phenyl2-(1,2,3,4-tetraydro-6-naphthyl)butyrate,

(13) 4-(2carboxy-2-methylpropylmercapto)phenyl2-(1-methyl-2-pyrrole)butyrate,

(14) 4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2l-methyl-2-pyrrole)butyrate,

(15) N-t-butoxy-3-(4bromophenylthio)propionamide,

(16) N-1-butoxy-3-(4-biphenylthio)propionamide.)

or non-toxic salts thereof, and

processes for the preparation of aryl (sulfide, sulfoxide, sulfone)derivatives and non-toxic salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene include straight andbranched isomers. The double bonds in the alkenylene group include E, Zand EZ mixture. Isomers produced by the existence of asymmetric carbonatoms are included in the present invention when branched-chain alkyl,alkoxy and alkylene etc. exist.

In the formula (I), C1-4 alkyl represented by R¹, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, or C1-4alkyl as a substituent of Ar₁ group and heterocyclic ring represented byA, J and E taken together, means methyl, ethyl, propyl, butyl and theisomers thereof.

In the formula (I), C1-8 alkyl represented by R², R³, R⁴, R⁷, R⁸, R⁹, A,means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and theisomers thereof.

In the formula (I), C1-15 alkyl as a substituent of Ar group, meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and theisomers thereof.

In the formula (I), C1-4 alkyl substituted by phenyl represented by R⁷,R⁸, R⁹, R¹⁵, R¹⁹, means methyl, ethyl, propyl, butyl and the isomerssubstituted by one phenyl.

In the formula (I), C1-4 alkoxy in R³ or R^(4,) or C1-4 alkoxy as asubstituent of heterocyclic ring represented by A, J and E takentogether, means methoxy, ethoxy, propoxy, butoxy and the isomersthereof.

In the formula (I), C1-15 alkyl as a substituent of Ar group, meansmethoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy,tetradecyloxy, pentadecyloxy and the isomers thereof.

In the formula (I), halogen as a substituent of Ar group or Ar₁ group,or halogen represented by A, J and E taken together, or halogen as asubstituent of heterocyclic ring represented by A, J and E takentogether, means fluoro, chloro, bromo and iodo.

In the formula (I), C3-7 cycloalkyl formed by R³ and R⁴ taken togetherwith the carbon to which they are attached, means cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In the formula (I), carbocyclic ring represented by Ar group, Ar, group,means C5-10 carbocyclic aryl or the above-mentioned C3-7 cycloalkyl. Forexample, C5-10 carbocyclic aryl includes benzene, pentalene, indene,naphthalene, azulene etc.

In the formula (I), heterocyclic ring represented by Ar group, Ar₁group, R³ or R⁴, heterocyclic ring represented by A, J and E takentogether and heterocyclic ring as a substituent of Ar group, means C5-15membered mono- or bi-heterocyclic ring containing 1-2 of nitrogen, 1 ofoxygen, 1 of sulfur. The heterocyclic ring includes partially or fullysaturated analogues of the above C5-15 membered mono- or bi-heterocyclicring containing 1-2 of nitrogen, 1 of oxygen, 1 of sulfur. For example,C5-15 membered mono- or bi-heterocyclic ring containing 1-2 of nitrogen,1 of oxygen, 1 of sulfur, includes pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan,pyran, oxepine, oxazepine, thiophene, thiaine (thiopyran), thiepine,oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiadiazine, thiadiazepine,indole, isoindole, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole,benzothiazole, benzoimidazole etc.

Also, partially or fully saturated C5-15 membered mono- orbi-heterocyclic ring containing 1-2 of nitrogen, 1 of oxygen, 1 ofsulfur, includes pyrroline, pyrrolidine, imidazoline, imidazolidine,pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine,tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine(dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran),dihydrooxazole, tetrahydrooxazole, dihydroisooxazole,tetrahydroisooxazole, dihydrothiazole, tetrahydrothiazole,dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazoleetc.

[Salts]

In the present invention, non-toxic salts includes all such salts. Forexample, non-toxic salts includes general salts, acid addition salts,hydrate salts etc.

The compounds of the present invention of the formula (I) may beconverted into the corresponding salts by known method. Non toxic andwater-soluble salts are preferable.

Suitable salts include the salts of alkali metal (potassium, sodiumetc.), alkaline-earth metal (calcium, magnesium etc.), ammonium salts,salts of organic amine which is pharmacologically permitted (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris (hydroxymethyl)aminomethane, lysine, arginine,N-methyl-D-gulcane etc.).

The compounds of the present invention of the formula (I) may beconverted into the corresponding acid-addition salts by known method.Non toxic and water-soluble salts are preferable.

Suitable acid-addition salts include the salts with inorganic acids suchas hydrochloric acid, hydrobromide, sulfate, phosphate, nitrate, and thesalts with organic acids such as acetic acid, trifluoroacetic acid,lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid,citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronicacid and gluconic acid.

The compounds of the present invention of the formula (I) or saltsthereof may be converted into a corresponding hydrate by methods knownper se.

In the compounds of the present invention of formula (I), the followingcompounds are preferred.

the formula (I-1)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-2)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-3)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-4)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-5)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-6)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-7)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-8)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-9)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-10)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-11)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-12)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-13)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-14)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-15)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-16)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-17)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-18)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-19)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-20)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-21)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-22)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-23)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-24)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-25)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-26)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-27)

(wherein all symbols are the same meanings as hereinbefore described.),

the formula (I-28)

(wherein A, J and E taken together, represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (inwhich R¹⁶ and R¹⁷ are the same meanings as hereinbefore described.),heterocyclic ring (this heterocyclic ring may be optionally substitutedby 1˜4 of C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, hydroxy,carboxyl, C1-8 alkoxycarbonyl, nitro, NR²⁴R²⁵ (in which R²⁴ and R²⁵ arethe same meanings as hereinbefore described.) or CONR²⁴R²⁵ (in which R²⁴and R²⁵ are the same meanings as hereinbefore described.).), the othersymbols are the same meanings as hereinbefore described.),

the formula (I-29)

(wherein A, J and E taken together, represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (inwhich R¹⁶ and R¹⁷ are the same meanings as hereinbefore described.),heterocyclic ring (this heterocyclic ring may be optionally substitutedby 1˜4 of C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, hydroxy,carboxyl, C1-8 alkoxycarbonyl, nitro, NR²⁴R²⁵ (in which R²⁴ and R²⁵ arethe same meanings as hereinbefore described.) or CONR²⁴R²⁵ (in which R²⁴and R²⁵ are the same meanings as hereinbefore described.).), the othersymbols are the same meanings as hereinbefore described.),

the formula (I-30)

(wherein A, J and E taken together, represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (inwhich R¹⁶ and R¹⁷ are the same meanings as hereinbefore described.),heterocyclic ring (this heterocyclic ring may be optionally substitutedby 1˜4 of C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, hydroxy,carboxyl, C1-8 alkoxycarbonyl, nitro, NR²⁴R²⁵ (in which R²⁴ and R²⁵ arethe same meanings as hereinbefore described.) or CONR²⁴R²⁵ (in which R²⁴and R²⁵ are the same meanings as hereinbefore described.).), the othersymbols are the same meanings as hereinbefore described.).

The compounds wherein n is 2, that is, the above compounds of theformulae (I-3), (I-6), (I-9), (I-12), (I-15), (I-18), (I-21), (I-24),(I-27) and (I-30) are more preferred. In the more preferred compounds,the compounds in which E is —CONH—, —CH₂—O—, —CH═CH—, ethynylene, and inwhich A, J and E taken together, represents heterocyclic ring, that is,the above compounds of the formulae (I-3), (I-15), (I-24), (I-27) and(I-30) (with proviso that A, J and E taken together, representsheterocyclic ring.) are particularly preferred.

Examples of representative compounds are shown in the following Tableand the compounds described in Example.

TABLE 1 (I-1a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 2 (I-2a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 3 (I-3a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 4 (I-4a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 5 (I-5a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 6 (I-6a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 7 (I-7a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 8 (I-8a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 9 (I-9a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 10 (I-10a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 11 (I-11a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 12 (I-12a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 13 (I-13a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 14 (I-14a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 15 (I-15a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 16 (I-16a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 17 (I-17a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 18 (I-18a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 19 (I-19a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 20 (I-20a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 21 (I-21a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 22 (I-22a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 23 (I-23a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 24 (I-24a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 25 (I-25a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 26 (I-26a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 27 (I-27a)

No. A R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH

TABLE 28 (I-28a)

No. A—J—E R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH 41

H COOH 42

H CONHOH 43

COOH 44

CONHOH 45

COOH 46

CONHOH 47

COOH 48

CONHOH 49

COOH 50

CONHOH 51

H COOH 52

H CONHOH 53

COOH 54

CONHOH 55

COOH 56

CONHOH 57

COOH 58

CONHOH 59

COOH 60

CONHOH

TABLE 29 (I-29a)

No. A—J—E R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH 41

H COOH 42

H CONHOH 43

COOH 44

CONHOH 45

COOH 46

CONHOH 47

COOH 48

CONHOH 49

COOH 50

CONHOH 51

H COOH 52

H CONHOH 53

COOH 54

CONHOH 55

COOH 56

CONHOH 57

COOH 58

CONHOH 59

COOH 60

CONHOH

TABLE 30 (I-30a)

No. A—J—E R⁴ R² 1 C₅H₁₁— H COOH 2 C₅H₁₁— H CONHOH 3 C₅H₁₁—

COOH 4 C₅H₁₁—

CONHOH 5 C₅H₁₁—

COOH 6 C₅H₁₁—

CONHOH 7 C₅H₁₁—

COOH 8 C₅H₁₁—

CONHOH 9 C₅H₁₁—

COOH 10 C₅H₁₁—

CONHOH 11

H COOH 12

H CONHOH 13

COOH 14

CONHOH 15

COOH 16

CONHOH 17

COOH 18

CONHOH 19

COOH 20

CONHOH 21

H COOH 22

H CONHOH 23

COOH 24

CONHOH 25

COOH 26

CONHOH 27

COOH 28

CONHOH 29

COOH 30

CONHOH 31

H COOH 32

H CONHOH 33

COOH 34

CONHOH 35

COOH 36

CONHOH 37

COOH 38

CONHOH 39

COOH 40

CONHOH 41

H COOH 42

H CONHOH 43

COOH 44

CONHOH 45

COOH 46

CONHOH 47

COOH 48

CONHOH 49

COOH 50

CONHOH 51

H COOH 52

H CONHOH 53

COOH 54

CONHOH 55

COOH 56

CONHOH 57

COOH 58

CONHOH 59

COOH 60

CONHOH

[Processes for the Preparation of the compound of the present invention]

The compounds of the present invention of the formula (I) may beprepared by the following methods, the methods described in Example, orknown methods.

In the compounds of the present invention of the formula (I), (A-1):thecompound in which n is 0, R² is —COOR⁷⁻¹ (in which R⁷⁻¹ is C1-8 alkyl,phenyl, or C1-4 alkyl substituted by phenyl, —OCOR²³ or —CONR²⁴R²⁵),substituents of Ar in A, and R³ and R⁴ are not —COOH, hydroxy, amino ora group containing them, and A, J and E taken together do not represent—COOH, i.e., the compound of the formula(I-A-1)

(wherein R³⁻¹ and R⁴⁻¹ are the same meanings as R³ and R⁴ respectively,with the proviso that R³⁻¹ and R⁴⁻¹ do not represent —COOH, hydroxy,amino or a group containing them; and A¹, J¹ and E¹ are the samemeanings as A, J and E respectively, with the proviso that substituentsof Ar in A are not —COOH, hydroxy or amino and A, J and E taken togetherdo not represent —COOH, and the other symbols are the same meanings ashereinbefore described.) may be prepared by the following methods.

(1) The compound in which E¹ is —CONR⁹—, may be prepared by amidation ofthe compound of the formula (II)

(wherein all the symbols are the same meanings as hereinbeforedescribed.)

with the compound of the formula (III)

A¹—J¹—COOH  (III)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

The method of amidation is known. It is includes the method

(1) via an acid halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent etc.

These methods are explained as follows.

(1) The method via an acid halide may be carried out, for example, byreacting a carboxylic acid with an acid halide (e. g., oxalyl chloride,thionyl chloride etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) or without asolvent at from −20° C. to the reflux temperature, and then by reactingthe obtained acid halide with an amine in the presence of a tertiaryamine (e. g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine etc.) in an organic solvent (e. g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) at atemperature of from 0° C. to 40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e. g.,pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate,isobutyl chloroformate etc.) in the presence of a tertiary amine (e. g.,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) inan organic solvent (e. g., chloroform, methylene chloride, diethylether, tetrahydrofuran etc.) or without a solvent at a temperature offrom −20° C. to 40° C., and then by reacting the obtained mixture ofacid anhydride with a corresponding amine in an organic solvent (e. g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), ata temperature of from 0° C. to 40° C.

(3) The method using a condensing agent (e. g.,1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 2-chloro-1-methylpyridinium iodide etc.) may becarried out, for example, by reacting a carboxylic acid with an amineusing a condensing agent in the presence or absence of a tertiary amine(e. g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridineetc.), in an organic solvent (e. g., chloroform, methylene chloride,dimethyl formamide, diethyl ether etc.) or without a solvent at atemperature of from 0° C. to 40° C.

The reactions (1), (2) and (3) hereinbefore described may be preferablycarried out in an atmosphere of inert gas (e. g., argon, nitrogen etc.)under anhydrous conditions.

(2) The compound in which E¹ is —NR⁹CO, may be prepared by amidation ofthe compound of formula (IV)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (V)

A¹—J¹—NHR⁹  (V)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

The amidation may be carried out by methods hereinbefore described.

(3) The compound in which E¹ is —OCO, may be prepared by esterificationof the compound of the formula (IV)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (VI)

A¹—J¹—OH  (VI)

(wherein all the symbols are the same meanings as hereinbeforedescribed.)

The method of esterification is known. It is includes the method

(1) via an acid halide,

(2) via a mixed acid anhydride,

(3) using a condensing agent etc.

These methods are explained as follows.

(1) The method via an acid halide may be carried out, for example, byreacting a carboxylic acid with an acid halide (e. g., oxalyl chloride,thionyl chloride etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) or without asolvent at from −20° C. to the reflux temperature, and then by reactingthe obtained acid halide with an alcohol in the presence of a tertiaryamine (e. g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine etc.) in an organic solvent (e. g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) at atemperature of from 0° C. to 40° C.

(2) The method via a mixed acid anhydride may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e. g.,pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acidderivative (e. g., ethyl chloroformate, isobutyl chloroformate etc.) inthe presence of a tertiary amine (e. g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine etc.) in an organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.)or without a solvent at a temperature of from 0° C. to 40° C., and thenby reacting the obtained mixture of acid anhydride with an alcohol in anorganic solvent (e. g., chloroform, methylene chloride, diethyl ether,tetrahydroturan etc.), at a temperature of from 0° C. to 40° C.

(3) The method using a condensing agent (e. g.,1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 2-chloro-1-methylpyridinium iodide etc.) may becarried out, for example, by reacting a carboxylic acid with an alcoholusing a condensing agent in the presence or absence of a tertiary amine(e. g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridineetc.), in an organic solvent (e. g., chloroform, methylene chloride,dimethyl formamide, diethyl ether etc.) or without a solvent at atemperature of from 0° C. to 40° C.

The reactions (1), (2) and (3) hereinbefore described may be preferablycarried out in an atmosphere of inert gas (e. g., argon, nitrogen etc.)under anhydrous conditions.

(4) The compound in which E¹ is —COO—, may be prepared by esterificationof the compound of the formula (VII)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (III)

A¹—J¹—COOH  (III)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

The esterification may be carried out by methods hereinbefore described.

(5) The compound in which E¹ is —CH₂—O—, may be prepared byetherification of the compound of the formula (VII)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (VIII)

(wherein X is halogen or trifluoromethanesulfonyloxy, the other symbolsare the same meanings as hereinbefore described.). The etherification isknown and may be carded out, for example, in an organic solvent (e.g.,dimethylformamide, acetone etc.), in the presence of base (e.g.,potassium carbonate etc.), at a temperature of from 0° C. to 40° C.

(6) The compound in which E¹ is —CO—CH₂—, —(CH₂)₂—, —CH═CH— or —C≡C—, orin which A¹, J¹ and E¹ taken together represents heterocyclic ring (thisheterocyclic ring may be substituted by 1-4 of C1-4 alkyl, C1-4 alkoxy,halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro,NR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings as hereinbeforedescribed.) or CONR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings ashereinbefore described.)), may be prepared by reduction of the compoundof the formula (AA)

(wherein E^(1A) is —CO—CH₂—, —(CH₂)₂—, —CH═CH— or —C≡C—, or A¹, J¹ andE^(1A) taken together represents heterocyclic ring (this heterocyclicring may be substituted by 1-4 of C1-4 alkyl, C1-4 alkoxy, halogen,trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro, NR²⁴R²⁵(in which R²⁴ and R²⁵ are the same meanings as hereinbefore described.)or CONR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings as hereinbeforedescribed.), the other symbols are the same meanings as hereinbeforedescribed.).

The reduction is known and may be carried out, for example, using ahydrogen donor (e.g., triethylsilane, trichlorosilane etc.) in anorganic solvent (e.g., trifluoroacetic acid etc.) at a temperature offrom 0° C. to 40° C., or this reaction may be also carried out byhydrogenolysis hereinafter described.

(7) The compound in which A¹, J¹ and E¹ taken together representsmethyl, halogen, trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy,NR¹⁶R¹⁷, may be prepared by the reaction of the compound of the formula(IX)

(wherein A¹, J¹ and E1B taken together represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (inwhich R¹⁶ and R¹⁷ are the same meanings as hereinbefore described.), theother symbols are the same meanings as hereinbefore described.) with thecompound of the formula (XA), formula (XB), formula (XC) or formula (XD)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

This reaction is known and may be carried out, for example, in anorganic solvent (e.g., diisopropylethylamine, tetrahydrofuran, ethanol,chloroform, acetonitrile etc.) in the presence of base catalyst (e.g.,triethylamine, tetrabutylammonium fluoride, morpholine, n-butyllithiumetc.), at a temperature of from 0° C. to 40° C.

(A-2): the compound in which n is 1 or 2, R² is —COOR⁷⁻¹ (in which R⁷⁻¹is the same meaning as hereinbefore described.), substituents of Ar inA, and R³ and R⁴ are not —COOH, hydroxy, amino or a group containingthem, A, J and E taken together do not represent —COOH, i.e., thecompound of the formula (I-A-2)

(wherein n1 is 1 or 2, all the other symbols are the same meanings ashereinbefore described.) may be prepared by the following methods.

(1) The compound in which n¹ is 1 or 2, E¹ is —CONR⁹—, —NR⁹CO—, —OCO—,—COO—, —CH₂—O—, and A¹, J¹ and E¹ taken together do not represent —COOH,may be prepared by oxidation of the compound of the formula (I-A-1a)

(wherein E¹⁻¹ is —CONR⁹—, —NR⁹CO—, —OCO—, —COO—, —CH₂—O—, or A, J¹ andE¹⁻¹ taken together represents methyl, halogen, trifluoromethyl, nitro,cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ (in which R¹⁶ and R¹⁷ are thesame meanings as hereinbefore described.), the other symbols are thesame meanings as hereinbefore described.).

The oxidation is known and may be carried out, for example, in anorganic solvent (e.g., methylene chloride, chloroform etc.) in thepresence of peracid (e.g., m-chloroperbenzoic acid etc.) at atemperature of from 0° C. to 40° C.; or using oxidizing agent (e.g.,periodic acid·2 hydrate etc.) in a solvent (carbon tetrachloride,acetonitrile, water, ethanol or mixture solvent thereof etc.), in thepresence or absence of catalyst (e.g., ruthenium (III) chloride hydrateetc.) at a temperature of from 0° C. to reflux temperature.

(2) The compound in which ni is 1 or 2, E¹ is —C≡—C—, or A, J and Etaken together represents heterocyclic ring (this heterocyclic ring maybe substituted by 1-4 of C1-4 alkyl, C1-4 alkoxy, halogen,trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro, NR²⁴R²⁵(in which R²⁴ and R²⁵ are the same meanings as hereinbefore described.)or CONR²⁴R²⁵ (in which R²⁴ and R²⁵ are the same meanings as hereinbeforedescribed.)), may be prepared by reaction of the compound of the formula(XI)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (XII)

A¹—J¹—≡  (XII)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) or the corresponding heterocyclic ring compound.

This reaction is known and may be carried out, for example, using acatalyst (e.g., tetrakis(triphenylphosphine)palladium etc.) in anorganic solvent (e.g., acetonitrile, tetrahydrofuran etc.) in thepresence of base (e.g., triethylamine etc.) and copper(I) iodide, at atemperature of from 0° C. to reflux temperature.

(3) The compound in which n1 is 2, E¹ is —CO—CH₂—, may be prepared byreaction of the compound of the formula (XIII)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of the formula (XA), formula (XB), formula(XC) or formula (XD)

(wherein all the symbols are the same meanings ass hereinbeforedescribed.); or may be prepared by treating the compound prepared inabove (2) with trifluoroacetic acid.

This reaction is known and may be carried out, for example, by refluxingwith heating, in an organic solvent (e.g., ethanol, mixture solvent ofwater and benzene etc.), in the presence of acetic acid or poly ethyleneglycol.

(4) The compound in which n1 is 2, En is —CH═CH—, may be prepared bydehydration of the compound of the formula (XIV)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

The dehydration is known and may be carried out, for example, byrefluxing with heating, in an organic solvent (erg., toluene, benzeneetc.), in the presence of catalytic quantity of p-toluenesulfonic acid.

(5) The compound in which n1 is 2, E¹ is —(CH₂)₂—, may be prepared byreduction of the compound of the formula (XIV)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

The reduction may be carried out by method as hereinbefore described, orthis reaction may be carried out by hydrogenolysis as hereinafterdescribed. (6) The compound in which n1 is 1, E¹ is —CO—CH₂—, —(CH₂)₂—,—CH═CH—, may be prepared by reduction of the compound (n1 is 2, and E¹is —CO—CH₂—, —(CH₂)₂—, —CH═CH—.) prepared in above (3)˜(5).

The reduction may be carried out by method as hereinbefore described, orthis reaction may be carried out by hydrogenolysis as hereinafterdescribed.

The compound in which n1 is 1, E¹ is —CO—CH₂—, may be prepared bytreating the compound (wherein n is 1, E¹ is —C≡C—.) prepared in above(2) with trifluoroacetic acid.

(7) In the compounds hereinbefore prepared in (1)˜(6), the compound inwhich R³⁻¹ is hydrogen, R⁴⁻¹ is

(in which R^(b-1) is —COOR²² or —COR²² (in which R²² is the same meaningas hereinbefore described.), the other symbols are the same meanings ashereinbefore described.), may be prepared by amidation of the formula(BB)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the corresponding carboxylic acid of the formula (CC)

(wherein all the symbols are the same meanings as hereinbeforedescribed.).

If necessary, it may be prepared by amidation of the correspondingcarboxylic acid of the formula (CC) with the compound obtained bydeprotection of protecting group (R^(b-1)) of amino under acidiccondition of compound prepared in above reaction.

The amidation may be carried out by methods as hereinbefore described.The deprotection of protecting group of amino under acidic condition maybe carried out by methods as hereinafter described.

(B) The compounds in which at least one of —COOR⁷ in R², and R³, R⁴, andsubstituents of Ar in A, and a group represented by A, J and E takentogether, represents —COOH or a group containing —COOH; or at least oneof R³, R⁴, and substituents of Ar in A, represents hydroxy, amino or agroup containing them, i.e., the compounds of the formula (I-B)

(wherein A², J², E², R³⁻², R^(4-2,) R⁷⁻² are the same meanings as A, J,E, R³, R⁴, R⁷ respectively, with proviso that at least one of —COOR⁷,and R³, R⁴, and substituents of Ar in A, and a group represented by A, Jand E taken together, represents —COOH or a group containing them; or atleast one of R³, R⁴, and substituents of Ar in A, represents hydroxy,amino or a group containing them; the other symbols are the samemeanings as hereinbefore described.) may be prepared by deprotectionunder alkaline or acidic conditions, or hydrogenolysis of the compoundof the formula (I-A-1) and the formula (I-A-2).

Deprotection under alkaline conditions is known and may be carried out,for example, in an organic solvent (e.g., methanol, tetrahydrofuran,dioxane etc.), using an alkali metal hydroxide (e.g., sodium hydroxide,potassium hydroxide etc.), an alkali earth metal hydroxide (e.g.,calcium hydroxide etc.) or a carbonate (e.g., sodium carbonate,potassium carbonate etc.), an aqueous solution thereof or a mixturethereof, at a temperature of from 0° C. to 40° C.

Deprotection under acidic conditions is known and may be carried out,for example, in a solvent (e.g., dichloro methane, dioxane, ethylacetate, acetic acid water or a mixture solvent thereof etc.), using anorganic acid (e.g., trifluoroacetic acid etc.) or an inorganic acid(e.g., hydrogen chloride, hydrogen bromide etc.) at a temperature offrom 0° C. to 120° C.

Hydrogenolysis is known and may be carried out, for example, in asolvent (e.g., ether (e.g., tetrahydrofuran, dioxane, diemethoxyethane,diethyl ether etc.), alcohol (e.g., methanol, ethanol etc.), abenzene-type solvent (e.g., benzene, toluene etc.), ketone (etc.acetone, methylethylketone etc.), nitorile (acetonitrile etc.), amide(dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixtureof two or more thereof, in the presence of a catalyst (e.g., palladiumon carbon, palladium black, palladium hydroxide, platinum dioxide,Raney-nickel etc.), in the presence or absence of an inorganic acid(e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid,tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid,p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acidetc.), at ordinary or elevated pressure of hydrogen gas or ammoniumformate at a temperature of from 0° C. to 200° C.

(C) The compounds, in which R² is —CONHOR⁸⁻¹ (in which R⁸⁻¹ is C1-8alkyl, phenyl, or C1-4 alkyl substituted by phenyl.); substituents of Arin A, R³ and R⁴ do not represent —COOH, hydroxy, amino or a groupcontaining them; A, J and E taken together do not represent —COOH, i.e.,the compounds of the formula (I-C)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) may be prepared by the following methods.

(1) The compound in which n is 0, may be prepared by condensation of thecompound of the formula (XV)

(wherein all the symbols are the same meanings as hereinbeforedescribed.) with the compound of formula (XVI)

(wherein R^(Y) is hydrogen or protection group of amino, the othersymbols are the same meanings as hereinbefore described.).

The condensation is known and may be carried out, for example, in anorganic solvent (e.g., chloroform, methylene chloride,dimethylformamide, tetrahydrofuran etc.) or without a solvent,optionally using a tertiary amine (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine etc.), using a condesing agent(e.g., 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) etc.), at atemperature of from 0° C. to 40° C.

(2) The compound in which n is 1 or 2, may be prepared by oxidation ofthe compound of the formula (I-C-1) prepared in above (1)

(wherein all the symbols are the same meanings as hereinbeforedescribed.), if necessary, followed by deprotection of R^(Y).

The oxidation may be carried out by methods as hereinbefore described.

The deprotection of R^(Y) is known and may be carried out, for example,in a solvent (e.g., methylene chloride, dioxane, ethyl acetate, aceticacid water or a mixture solvent thereof etc.), using an organic acid(e.g., trifluoroacetic acid etc.) or an inorganic acid (e.g., hydrogenchloride, hydrogen bromide etc.) at a temperature of from 0° C. to 120°C.; or in a solvent (e.g., ether (e.g., tetrahydrofuran, dioxane,diemethoxyethane, diethyl ether etc.), alcohol (e.g., methanol, ethanoletc.), a benzene-type solvent (e.g., benzene, toluene etc.), ketone(etc. acetone, methylethylketone etc.), nitorile (acetonitrile etc.),amide (dimethyliormamide etc.), water, ethyl acetate, acetic acid or amixture of two or more thereof), in the presence of a catalyst (e.g.,palladium on carbon, palladium black, palladium hydroxide, platinumdioxide, Raney-nickel etc.), in the presence or absence of an inorganicacid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boricacid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid,p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acidetc.), at ordinary or elevated pressure of hydrogen gas or ammoniumformate at a temperature of from 0° C. to 200° C. When an acid is used,a salt thereof may be used.

(D) The compounds in which PB in PB is hydrogen, in which at least oneof R³, R⁴, and substituents of Ar in A, or a group represented by A, Jand E taken together, represents —COOH or a group containing —COOH, andin which at least one of R³, R⁴, and substituents of Ar in A, representshydroxy, amino or a group containing them, i.e., the compounds of theformula (I-D)

(wherein A², J², E², R³⁻², R⁴⁻², R⁸⁻² are the same meanings as A, J, E,R³, R⁴, R⁸ respectively, with the proviso that at least one of R³, R⁴,substituents of Ar in A, or a group represented by A, J and E takentogether, represents —COOH or a group containing —COOH; at least one ofR³, R⁴, substituents of Ar in A, represents hydroxy, amino or a groupcontaining them; or R⁸ is hydrogen, the other symbols are the samemeanings as hereinbefore described.) may be prepared by deprotectionunder alkali or acidic conditions, or hydrogenolysis of the compound ofthe formula (I-C).

The deprotection under alkali or acidic conditions, or hydrogenolysis,may be carried out by the methods as hereinbefore described.

The compounds of formulae (II), (IV), (VII), (XI) or (XIV) may beprepared by known methods, methods described in the following schemes 1,2, 3, 4 and 5 or methods described in Example.

In the schemes, R^(Z) is protection group of carboxylic acid, the othersymbols are the same meanings as hereinbefore described.

Each reaction in the above schemes, may be carried out by known methods.In the above schemes, the compounds used as starting materials are knownper se, or may be easily prepared by known methods. The other startingmaterials and reagents in the present invention are known per se or maybe prepared by known methods.

In each reaction in the present invention, products may be purified byconventional techniques. For example, purification may be carried out bydistillation at atmospheric or reduced pressure, by high performanceliquid chromatography, by thin layer chromatography or by columnchromatography using silica gel or magnesium silicate, by washing or byrecrystallization. Purification may be carried out after each reaction,or after a series of reactions.

Possibility of Industrial use

[Pharmacological Activity]

The potency of inhibitory activity of the compounds of the formula (I)against matrix metalloproteinases is confirmed by the followingexperiment. For example, with respect to inhibitory activity againstgelatinase A, the following results are obtained.

(1) Inhibitory activity against gelatinase A.

Experimental method

The progelatinase A (7 μl; in assay buffer (90 μl) was purified fromhuman normal skin dermal fibroblasts (HNDF). It was activated by theaddition of 10 mM APMA (10 μl) for 1 hour at 37° C. The solution ofactivated gelatinase A (1 U/tube, 98 μl) was mixed with the solution ofvarious concentrations of the test compound or the solution in which thetest compound is not added, (2 μl), and 0.05% FITC-gelatin (100 μl) andincubated for 2 hours at 37° C. The enzymatic reaction was terminated bythe addition of 2 M Tris-HCI (pH 9.5) containing 94.7% ethanol (750 el).The mixture was stirred and then allowed to stand for 30 minutes at 0°C. The mixture was centrifuged for 30 minutes at 900×g. Inhibitoryactivity against gelatinase was determined by measuring the fluorescentintensity in supernatant (Ex=495 nm, and Em=520 nm). The results areshown in Table 31.

TABLE 31 Example No. IC50 (μM)  8(2) 0.54  8(7) 0.40 19(1) 0.011 280.013 28(1) 0.0014 28(3) 0.0029

In the above experimental method, APMA is p-aminophenylmercuric acetateand FITC is fluorescein isothiocyanate.

[Toxicity]

On the other hand, the toxicity of the compounds of the presentinvention is very low and therefore it may be confirmed that thecompounds are safe for pharmaceutical use.

[Application for Pharmaceuticals]

Inhibition of matrix metalloproteinases is useful for prevention and Ior treatment of rheumatoid diseases, arthrosteitis, unusual boneresorption, osteoporosis, periodontitis, interstitial nephritis,arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury,metastasis of, invasion of or growth of tumor cells, autoimmune diseases(e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascularemigration or infiltration of leukocytes, arterialization etc.

For the purpose above described, the compounds of formula (I) of thepresent invention, non-toxic salts, acid addition salts or hydratesthereof may be normally by administered systemically or locally, usuallyby oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 1 mg to 100 mg, byparenteral administration (preferably intravenous administration), up toseveral times per day, or continuous administration from 1 to 24 hoursper day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid compositions, liquid compositions or othercompositions for oral administration, injections, liniments orsuppositories for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules.

Capsules include hard capsules and soft capsules.

In such solid compositions, one or more of the active compound(s) may beadmixed with at least one inert diluent (such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone or magnesium metasilicate aluminate). Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g., lubricating agents (such asmagnesium stearate), disintegrating agents (such as cellulose calciumglycolate), stabilizing agents (such as lactose), and agents to assistdissolution (such as glutamic acid or aspartic acid). The tablets orpills may, if desired, be coated with a film of gastric or entericmaterial (such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropylmethyl cellulose phthalate), or be coated with two or morefilms. And further, coating may include containment within capsules ofabsorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, syrups and elixirs. In such liquidcompositions, one or more of the active compound(s) may be contained inan inert diluent(s) commonly used in the art (e.g., purified water,ethanol). Besides inert diluents, such compositions may also compriseadjuvants (such as wetting agents or suspending agents), sweeteningagents, flavouring agents, perfuming agents, and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g., stabilizing agents (such assodium sulfate), isotonic buffer (such as sodium chloride, sodiumcitrate or citric acid). For preparation of such spray compositions, forexample, the method described in the U.S. Pat. Nos. 2,868,691 or3,095,355 may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. Aqueous solutions andsuspensions may include distilled water for injection or physiologicalsalt solution. Non-aqueous solutions and suspensions may includepropylene glycol, polyethylene glycol, vegetable oil such as olive oil,alcohol such as ethanol or POLYSORBATE80 (registered trade mark).Injections may comprise additional ingredients other than inertdiluents: e.g. preserving agents, wetting agents, emulsifying agents,dispersing agents, stabilizing agents (such as lactose), assistingagents such as agents to assist dissolution (e.g. glutamic acid oraspartic acid). They may be sterilized for example, by filtrationthrough a bacteria-retaining filter, by incorporation of sterilizingagents in the compositions or by irradiation. They may also bemanufactured in the form of sterile solid compositions which may bedissolved in sterile water or some other sterile diluent(s) forinjection immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments, ointment, suppositories for rectaladministration and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se.

REFERENCE EXAMPLE AND EXAMPLE

The following reference examples and examples illustrate the presentinvention, but do not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations or TLC.

The solvents in the parentheses in NMR show the solvents used inmeasurement.

Example 1

3-(4-aminophenylthio)propionic acid t-butyl ester

To a solution of 4-aminothiophenol (2.36 g) in tetrahydrofuran (THF; 20ml), 2-propenoic acid t-butyl ester (3.51 ml) and 1.0Mtetrabutylammonium fluoride in THF solution (340 μl) were added. Themixture solution was stirred for 30 minutes at room temperature to givethe title compound. The compound was used for next reaction as such.

Example 1(1)˜1(4)

The following compounds were obtained by the same procedure as Example1, using the corresponding thiophenol derivatives and the correspondingcarboxylic acid derivatives.

Example 1(1)

3-(4-hydroxyphenylthio)propionic acid t-butyl ester

The prepared title compound was used for next reaction withoutpurification.

Example 1(2)

2-methyl-3-(4-hydroxyphenylthio)propionic acid t-butyl ester

TLC: Rf 0.45 (hexane:ethyl acetate=7:3),

NMR (CDCl₃+CCl₄ (5 drops)): δ 7.31 (2H, d, J=8.8 Hz), 6.77 (2H, d, J=8.8Hz), 55.82 (1H, s), 3.08 (1H, dd, J=1 3.2 Hz, 7.8 Hz), 2.77 (1H, dd, J=13.2 Hz, 6.6 Hz), 2.53 (1H, m), 1.47 (9H, s), 1.20 (3H, d, J=7.2 Hz).

Example 1(3)

2-benzyl-3-(4-bromophenylthio)propionic acid t-butyl ester

TLC: Rf 0.58 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.36 (2H, d, J=8.8 Hz), 7.30-7.10 (7H, m), 3.11 (1H, dd,J=14.0 Hz, 8.1 Hz), 3.00-2.70 (4H, m), 1.36 (9H, s).

Example 1(4)

3-(4-methoxyphenylthio)propionic acid t-butyl ester

The prepared title compound was used for next reaction withoutpurification.

Example 2

3-[4-(benzoylamino) phenylthio]propionic acid t-butyl ester

Triethylamine (3.3 ml) and benzoyl chloride (2.0 ml) were added to thecompound prepared in Example 1 and the reaction solution was stirred for30 minutes at room temperature. 1 N hydrochloric acid was added to thereaction solution. The reaction solution was extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium bicarbonate, water, a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated. Theresidue was washed with ether to give the title compound (5.17 g).

TLC: Rf 0.51 (hexane:ethyl acetate=7:3),

NMR (CDCl₃): δ 7.92 (1H, s), 7.89-7.82 (2H, m), 7.60 (2H, d, J=8.8 Hz),7.56-7.42 (3H, m), 7.38 (2H, d, J=8.8 Hz), 3.08 (2H, t, J=7.4 Hz), 2.51(2H, t, J=7.4 Hz), 1.45 (9H, s).

Example 3

3-(4-benzyloxyphenylthio)propionic acid t-butyl ester

A mixture solution of the compound prepared in Example 1(1) (3.29 g),benzyl bromide (2.3 ml), potassium carbonate (3.58 g) anddimethylformamide (15 ml) was stirred overnight at room temperature. Thereaction solution was extracted with ethyl acetate. The extract waswashed with water and a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated to give thetitle compound (2.20 g) having the following physical data.

TLC: Rf 0.71 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.46-7.30 (7H, m), 6.90 (2H, d, J=9.0 Hz), 5.04 (2H, s),3.00 (2H, t, J=7.6 Hz), 2.46 (2H, t, J=7.6 Hz), 1.44 (9H, s).

Example 4

3-[4-(benzoylamino)phenylsulfinyl]propionic acid t-butyl ester

To a solution of the compound prepared in Example 2 (714 mg) inchloroform (7 ml), m-chloroperbenzoic acid (493 mg) was added and thereaction solution was stirred for 30 minutes at room temperature. Thereaction solution was washed with a saturated aqueous solution of sodiumbicarbonate and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated. Ether was added tothe residue and the crystal was filtered off and then the title compound(616 mg) having the following physical data was obtained.

TLC: Rf 0.37 (chloroform:methanol=19:1),

NMR (CDCl₃): δ 8.17 (1H, s), 7.94-7.86 (2H, m), 7.85 (2H, d., J=8.8 Hz),7.61 (2H, d, J=8.8 Hz), 7.57-7.46 (3H, m), 3.15 (1H, ddd, J=6.6 Hz, 8.8Hz, 13.2 Hz), 2.93 (1H, ddd, J=5.8 Hz, 8.2 Hz, 13.2 Hz), 2.73 (1H, ddd,J=6.6 Hz, 8.2 Hz, 14.4 Hz), 2.43 (1H, ddd, J=5.8 Hz, 8.8 Hz, 14.4 Hz),1.43 (9H, s).

Example 5

3-[4-(benzoylamino)phenylsulfonyl]propionic acid t-butyl ester

Under an atmosphere of argon, to a mixture solution of the compoundprepared in Example 2 (714 mg) in carbon tetrachloride (2 ml),acetonitrile (2 ml) and water (4 ml), periodic acid·2 hydrates (958 mg)and ruthenium (III) chloride·hydrate (8 mg) were added and reactionmixture was stirred for 2 hours. Water was added to the reaction mixtureand it was extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium thiosulfate and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography(hexane:ethyl acetate=3:2) to give the title compound (730 mg) havingthe following physical data.

TLC: Rf 0.20 (hexane:ethyl acetate=7:3),

NMR (CDCl₃): δ 8.11 (1H, s), 7.94-7.86 (6H, m), 7.65-7.47 (3H, m), 3.37(2H, t, J=7.4 Hz), 2.65 (2H, t, J=7.4 Hz), 1.41 (9H,s).

Example 5(1)˜5(2)

The following compounds were obtained by the same procedure as Example5, using compounds prepared in Example 3 and Example 1(3)

Example 5(1)

3-[4-(benzyloxy)phenylsulfonyl]propionic acid t-butyl ester

TLC: Rf 0.33 (hexane:ethyl acetate=7:3),

NMR (CDCl₃): δ 7.83 (2H, d, J=9.2 Hz), 7.42-7.32 (5H, m), 7.09 (2H, d,J=9.2 Hz), 5.14 (2H, s), 3.34 (2H, t, J=7.4 Hz), 2.64 (2H, t, J=7.4 Hz).

Example 5(2)

2-benzyl-3-(4-bromophenylsulfonyl)propionic acid t-butyl ester

TLC: Rf 0.30 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.69 (2H; d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.30-7.20(3H, m), 7.07 (2H, s), 3.63 (1H, m), 3.10-2.90 (3H, m), 2.90 (1H, m),1.33 (9H, s).

Reference Example 1

2-methyl-3-[4-(trifluoromethanesulfonyloxy)phenylthio]propionic acidt-butyl ester

Under an atmosphere of argon and at −78° C., to a solution of thecompound prepared in Example 1(2) (1.50 g) in dichioromethane (10 ml),pyridine (1.1 3 ml) and anhydrous trifluoromethanesulfonic acid (1.13ml) were added dropwise. The mixture solution was stirred for 2 hours atroom temperature. A saturated aqueous solution of sodium bicarbonate (20ml) was added to the reaction mixture and it was vigorously stirred for1 hour at room temperature. The reaction mixture was extracted withethyl acetate. The extract was washed with 1N hydrochloric acid, asaturated aqueous solution of sodium bicarbonate, a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography(hexane:ethyl acetate=19: 1) to give the title compound (2.05 g) havingthe following physical data.

TLC: Rf 0.29 (hexane:ethyl acetate=19:1),

NMR (CDCl₃+CCl₄ (5 drops)): δ 7.40 (2H, d, J=9.0 Hz), 7.19 (2H, d, J=9.0Hz), 3.24 (1H, dd, J=13.2 Hz, 7.3 Hz), 2.91 (1H, dd, J=13.2 Hz, 6.8 Hz),2.59 (1H, m), 1.45 (9H, s), 1.24 (3H, d, J=6.8 Hz).

Reference Example 2

2-methyl-3-(4-trifluoromethanesulfonyloxyphenylsulfonyl)propionic acidt-butyl ester

The title compound (748 mg) having the following physical data wasobtained by the same procedure as Example 5, using the compound preparedin Reference example 1 (1.00 g).

mp:50° C.,

TLC: Rf 0.57 (hexane:ethyl acetate=9:1),

NMR (CDCl₃+CCl₄ (5 drops)): δ 8.05 (2H, d, J=8.6 Hz), 7.49 (2H, d, J=8.6Hz), 3.71 (1H, dd, J=14.2 Hz, 7.6 Hz), 3.06 (1H, dd, J=14.2 Hz, 5.1 Hz),2.96 (1H, m), 1.42 (9H, s), 1.31 (3H, d, J=7.2 Hz).

Example 6

3-(4-bromophenylsulfonyl)propionic acid t-butyl ester

The mixture of 4-bromophenylsulfinic acid sodium salt (729 mg),2-propenoic acid t-butyl ester (439 μl), 95% ethanol (4 ml) and aceticacid (372 μl) was stirred for 12 hours at room temperature. Further,2-propenoic acid t-butyl ester (2.20 ml) was added to the mixture and itwas refluxed for 4 hours. The reaction mixture was diluted with ethylacetate. The mixture was washed with a saturated aqueous solution ofsodium bicarbonate, a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and concentrated to give thetitle compound (872 mg) having the following physical data.

mp: 105° C.,

TLC: Rf 0.31 (hexane:ethyl acetate=4:1),

NMR (CDCl₃+CCl₄ (5 drops)): δ 7.78 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8Hz), 3.38 (2H, t, J=7.3 Hz), 2.65 (2H, t, J=7.3 Hz), 1.40 (9H, s).

Example 7

2-methyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid t-butylester

To a solution of the compound prepared in Reference example 2 (432 mg)and 4-ethynyltoluene (133 μl) in acetonitrile (10 ml),triphenylphosphine (31 mg), triethylamine (2 ml), copper iodide (8 mg)and 10% palladium-carbon (43 mg) were added successively. The mixturewas refluxed for 3 hours and concentrated. The residue was purified bycolumn chromatography (hexane:ethyl acetate=17:3) to give the titlecompound (376 mg). The title compound (376 mg) was recrystallized fromhexane to give the title compound (227 mg) having the following physicaldata.

TLC: Rf 0.41 (hexane:ethyl acetate=4:1),

NMR (CDCl₃+CCl₄ (5 drops)): δ 7.88 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=8.6Hz), 7.45 (2H. d, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz), 3.68 (1H, dd,J=13.9 Hz, 7.1 Hz), 3.01 (1H, dd, J=13.9 Hz, 5.4 Hz), 2.89 (1H, m), 1.42(9H, s), 1.29 (3H, d, J=7.2 Hz).

Example 7(1)˜7(5)

The following compounds were obtained by the same procedure as Example7, using the compounds prepared in Example 6 or Example 5(2), and thecorresponding acetylene derivatives.

Example 7(1)

3-[4-(1-heptynyl)phenylsulfonyl]propionic acid t-butyl ester

TLC: Rf 0.38 (hexane:ethyl acetate=6:1),

NMR (CDCl₃+CCl₄ (5 drops)): δ 7.81 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6Hz), 3.37 (2H, t, J=7.6 Hz), 2.64 (2H, t, J=7.6 Hz), 2.44 (2H, t, J=7.1Hz), 1.59 (2H, m), 1.20-1.50 (4H, m), 1.41 (9H, s), 0.93 (3H, t, J=6.8Hz).

Example 7(2)

3-[4-(phenylethynyl)phenylsulfonyl]propionic acid t-butyl ester

TLC: Rf 0.59 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.89 (2H, d, J=8.7H), 7.70 (2H, d, J=8.7 Hz), 7.58-7.53(2H, m), 7.40-7.37 (3H, m), 3.40 (2H, t, J=7.8 Hz), 2.67 (2H, t, J=7.8Hz), 1.41 (9H, s).

Example 7(3)

3-[4-(2-pyridylethynyl)phenylsulfonyl]propionic acid 1-butyl ester

TLC: Rf 0.34 (hexane:ethyl acetate=1:1),

NMR (CDCl₃): δ 8.65 (1H, m), 7.92 (2H, d, J=8.6H), 7.78 (2H, d, J=8.6H),7.70 (1H, m), 7.56 (1H, m), 7.31 (1H, m), 3.42 (2H, m), 2.69 (2H, m),1.42 (9H, s).

Example 7(4)

3-[4-(4-methoxyphenylethynyl)phenylsulfonyl]propionic acid t-butyl ester

TLC: Rf 0.15 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.87 (2H, d, J=8.6H), 7.66 (2H, d, J=8.6H), 7.49 (2H, d,J=8.8H), 6.90 (2H, d, J=8.8H), 3.85 (3H, s), 3.40 (2H, m), 2.66 (2H, m),1.41 (9H, s).

Example 7(5)

2-benzyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid t-butylester

TLC: Rf 0.19 (hexane:ethyl acetate=4:1),

NMR (CDCl₃): δ 7.81 (2H, d, J=8.6 Hz), 7.64 (2H, d, J=8.6 Hz), 7.45 (2H,d, J=8.1 Hz),7.30-7.15 (5H, m), 7.08 (2H, m), 3.64 (1H, m), 3.15-2.75(4H, m), 2.40 (3H, s), 1.34 (9H, s).

Example 8

3-[4-(benzoylamino)phenylthio]propionic acid

A solution of the compound prepared in Example 2 (560 mg) intrifluoroacetic acid (5 ml) was stirred for 1 hour at room temperature.The reaction solution was concentrated and benzene was added to theresidue, and then the solution was concentrated again. The residue waswashed with ether to give the title compound (440 mg) having thefollowing physical data.

TLC: Rf 0.19 (chloroform:methanol=9:1),

NMR (DMSO-d₆): δ 12.80-11.80 (1H, br.s), 10.30 (1H, s), 7.95 (2H, dd,J=2.0 Hz, 8.2 Hz), 7.77 (2H, d, J=8.8 Hz), 7.65-7.47 (3H, m), 7.36 (2H,d, J=8.8 Hz), 3.09 (2H, t, J=7.4 Hz), 2.50 (2H, t, J=7.4 Hz).

Example 8(1)˜8(11)

The following compounds were obtained by the same procedure as Example 8(deprotection under acidic condition; for example, a solution oftrifluoroacetic acid, hydrochloric acid in dioxane or ethyl acetate, areused.), using the compounds prepared in Example 4, 5, 5(1), 7, 7(1),7(2), 7(3), 7(4), 7(5) or 1(4).

Example 8(1)

3-[4-(benzoylamino)phenylsulfinyl]propionic acid

TLC: Rf 0.26 (chloroform:methanol=90:10:1),

NMR (DMSO-d₆): δ 12.80-11.80 (1H, br.s), 10.52 (1H, s), 8.01 (2H,d,J=8.8 Hz), 7.99-7.93 (2H, m), 7.64 (2H, d, J=8.8 Hz), 7.62-7.50 (3H,m), 3.20 (1H, ddd, J=6.8, 8.2, 13.6 Hz), 2.95 (1H, ddd, J=6.2,8.2,13.6Hz), 2.58 (1H, ddd, J=6.8,8.2,16.8 Hz), 2.33 (1H, ddd, J=6.2,8.2,16.8Hz).

Example 8(2)

3-[4-(benzoylamino)phenylsulfonyl]propionic acid

TLC: Rf 0.33 (chloroform:methanol:acetic acid 90:10:1),

NMR (DMSO-d₆): δ 13.20-11.80 (1H, br.s), 10.68 (1H, s), 8.07 (2H, d,J=8.8 Hz), 7.98 (2H, dd, J=1.8,8.2 Hz), 7.87 (2H, d, J=8.8 Hz),7.70-7.50 (3H m), 3.48 (2H, t, J=7.2 Hz), 2.53 (2H, t, J=7.2 Hz).

Example 8(3)

3-[4-(benzyloxy)phenylsulfonyl]propionic acid

TLC: Rf 0.63 (chloroform:methanol:acetic acid 90:10:1),

NMR (DMSO-d₆): δ 12.70-12.40 (1H, br.s), 7.82 (2H, d, J=8.8 Hz),7.52-7.30 (5H, m), 7.28-7.20 (2H, d, J=8.8 Hz), 5.22 (2H, s), 3.46 (2H,t, J=7.4 Hz), 2.50 (2H, t, J=7.4 Hz).

Example 8(4)

2-methyl-3-[4-(4-tolylcarbonylmethyl)phenylsulfonyl]propionic acid

TLC: Rf 0.33 (chloroform:methanol:acetic acid=40:1:0.2),

NMR (DMSO-d₆+CCl₄ (5 drops)): δ 12.58 (1H, s), 7.97 (2H, d, J=7.8 Hz),7.84 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=7.8 Hz),3.60 (1H, dd, J=14.2, 6.8 Hz), 3.39 (1H, dd, J=14.2, 5.4 Hz), 2.68 (1H,m), 2.39 (3H, s), 1.17 (3H, d, J=7.1 Hz).

Example 8(5)

2-methyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.35 (chloroform:methanol=10:1),

NMR (DMSO-d₆+CCl₄ (5 drops)): δ 12.57 (1H, s), 7.91 (2H, d, J=8.6 Hz),7.79 (2H, d, J=8.6 Hz), 7.50 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz),3.66 (1H, dd, J=14.4, 7.3 Hz), 3.44 (1H, dd, J=14.4, 5.4 Hz), 2.70 (1H,m), 2.36 (3H, s), 1.18 (3H, d, J=7.1 Hz).

Example 8(6)

3-[4-(1-heptynyl)phenylsulfonyl]propionic acid

mp: 122˜123° C.,

TLC: Rf 0.78 (chloroform:methanol:acetic acid=9:1:0.5),

NMR (DMSO-d₆+CCl₄ (5 drops)): δ 12.54 (1H, s), 7.84 (2H, d, J=8.2 Hz),7.63 (2H, d, J=8.2 Hz), 3.52 (2H, t, J=7.4 Hz), 2.40-2.60 (4H, m), 1.57(2H, m), 1.37 (4H, m), 0.90 (3H, t, J=7.0 Hz).

Example 8(7)

3-[4-(phenylethynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.47 (chloroform:methanol=4:1),

NMR (DMSO-d₆): δ 12.49 (1H, br.s), 7.93 (2H, d, J=8.5 Hz), 7.78 (2H, d,J=8.5 Hz), 7.61-7.56 (2H, m), 7.55-7.42 (3H, m), 3.52 (2H, t, J=7.3 Hz),2.56 (2H, t, J=7.3 Hz).

Example 8(8)

3-[4-(2-pyridylethynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.39 (chloroform:methanol:acetic acid=100:10:1),

NMR (CDCl₃+CD₃OD (3 drops)): δ 8.63 (1H, m), 7.94 (2H, d, J=8.6 Hz),7.83-7.73 (3H, m), 7.60 (1H, m), 7.36 (1H, m), 3.47 (2H, m), 2.75 (2H,m).

Example 8(9)

3-[4-(4-methoxyphenylethynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.42 (chloroform:methanol:acetic acid=100:10:1),

NMR (CDCl₃+CD₃OD (3 drops)): δ 7.87 (2H, d, J=8.6 Hz), 7.66 (2H, d,J=8.6 Hz), 7.50 (2H, d, J=9.0 Hz), 6.91 (2H, d, J=9.0 Hz), 3.85 (3H, s),3.44 (2H, m), 2.73 (2H, m).

Example 8(10)

2-benzyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.45 (chloroform:methanol:acetic acid=100:10:1),

NMR (CDCl₃+CD₃OD (3 drops)): δ 7.77 (2H, d, J=8.6 Hz), 7.62 (2H, d,J=8.6 Hz), 7.45 (2H, d, J=8.1 Hz), 7.30-7.15 (5H, m), 7.04 (2H, m), 3.67(1H, m), 3.15-3.05 (3H, m), 2.82 (1H, m), 2.40 (3H, s).

Example 8(11)

3-(4-methoxyphenylthio)propionic acid

TLC: Rf 0.48 (chloroform:methanol=10:1),

NMR (CDCl₃): δ 7.39 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 3.80 (3H,s), 3.04 (2H, t, J=7.2 Hz), 2.61 (2H, t, J=7.2 Hz).

Example 9

N-t-butoxy-3-(4-methoxyphenylthio)propionamide

To a solution of the compound prepared in Example 8(11) (1.00 g) in DMF(20 ml), t-butoxyamine hydrochloride (652 mg), triethylamine (0.8 ml),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) hydrochloride (995mg) and 1-hydroxybenzotriazole (HOBt) hydrate (795 mg) were added at 0°C. The mixture was stirred for 16 hours at room temperature. To thereaction mixture, ethyl acetate and water were added. The organic phasewas washed with 0.1 N hydrochloric acid, a saturated aqueous solution ofsodium bicarbonate, water and a saturated aqueous solution of sodiumchloride, successively, dried over anhydrous magnesium sulfate andconcentrated to give the title compound (1.35 g) having the followingphysical data.

TLC: Rf 0.76 (chloroform:methanol=10:1).

Example 9(1)

N-benzyloxy-3-(4-methoxyphenylthio)propionamide

The title compound (423 mg) having the following physical data wasobtained by the same procedure as Example 9, using the compound preparedin Example 8(11) (300 mg) and benzyloxyamine hydrochloride (271 mg).

TLC: Rf 0.65 (chloroform:methanol=10:1),

NMR (DMSO-d₆): δ 7.38 (5H, m), 7.33 (2H, d, J=8.6 Hz), 6.91 (2H, d,J=8.6 Hz), 4.77 (2H, s), 3.74 (3H, s), 3.01 (2H, t, J=7.4 Hz), 2.21 (2H,t, J=7.4 Hz).

Example 10

N-benzyloxy-3-(4-methoxyphenylsulfonyl)propionamide

The title compound (152 mg) having the following physical data wasobtained by the same procedure as Example 5, using the compound preparedin Example 9(1) (159 mg).

TLC: Rf 0.48 (chloroform:methanol=20:1).

Reference Example 3

N-t-butoxycarbonyl-N-t-butoxycarbonyloxy-3-(4-methoxyphenylthio)propionamide

To a solution of the compound prepared in Example 8(11) (106 mg) in DMF(5 ml), N-t-butoxycarbonyl-N-t-butoxycarbonyloxyamine (120 mg), EDChydrochloride (106 mg) and 4-(dimethylamino)pyridine (6 mg) were addedat 0° C. The mixture was stirred for 16 hours at room temperature. Tothe reaction solution, water was added and it was extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofammonium chloride, a saturated aqueous solution of sodium bicarbonate, asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate and concentrated to give the title compound (211 mg)having the following physical data.

TLC: Rf 0.48 (hexane:ethyl acetate=4:1).

NMR (DMSO-d₆): δ 7.35 (2H, d, J=8.6 Hz), 6.93 (2H, d, J=8.6 Hz), 3.74(3H, s), 3.18 (2H, m), 3.05 (2H, m), 1.46 (9H, s), 1.43 (9H, s).

Reference Example 4

N-t-butoxycarbonyl-N-t-butoxycarbonyloxy-3-(4-methoxyphenylsulfinyl)propionamide

The title compound (quant) having the following physical data wasobtained by the same procedure as Example 4, using the compound preparedin Reference example 3 (190 mg).

TLC: Rf 0.36 (chloroform:methanol=20:1),

NMR (DMSO-d₆): δ 7.58 (2H, d, J=8.6 Hz), 7.15 (2H, d, J=8.6 Hz), 3.83(3H, s), 3.28-3.08 (2H, m), 3.05-2.80 (2H, m), 1.46 (9H, s), 1.44 (9H,s).

Example 11

N-hydroxy-3-(4-methoxyphenylthio)propionamide

The mixture of the compound prepared in Example 9 (200 mg) and 30%hydrogen bromide in acetic acid (2 ml) was stirred for 1 hour at roomtemperature. The reaction mixture was concentrated. The residue waspurified by column chromatography (chloroform:methanol=10:1) to give thetitle compound (138 mg) having the following physical data.

TLC: Rf 0.33 (chloroform:methanol=10:1),

NMR(DMSO-d₆): δ 10.42 (1H, br.s), 8.79 (1H, s), 7.33 (2H, d, J=8.6 Hz),6.92 (2H, d, J=8.6 Hz), 3.75 (3H, s), 3.01 (2H, t, J=7.4 Hz), 2.20 (2H,t, J=7.4 Hz).

Example 11(1)˜11(2)

The following compounds were obtained by the same procedure as Example11 (deprotection under acidic condition; for example, hydrogen bromidein acetic acid, trifluoroacetic acid are used.), or the same desiredprocedure (hydrogenolysis) as Example 11, using the compounds preparedin Reference example 4 or Example 10.

Example 11(1)

N-hydroxy-3-(4-methoxyphenylsulfinyl)propionamide

TLC: Rf 0.46 (chloroform:methanol=4:1).

NMR (DMSO-d₆) δ 10.50 (1H, br.s), 8.82 (1H, br.s), 7.58 (2H, d, J=8.6Hz), 7.15 (2H, d, J=8.6 Hz), 3.82 (3H, s), 3.20-3.03 (1H, m), 3.00-2.83(1H, m), 2.43-2.25 (1H, m), 2.10-1.93 (1H, m).

Example 11 (2)

N-hydroxy-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.66 (chloroform:methanol=4:1),

NMR (DMSO-d₆): δ 10.50 (1H, br.s), 8.85 (1H, s), 7.82 (2H, d, J=8.6 Hz),7.17 (2H, d, J=8.6 Hz), 3.87 (3H, s), 3.43 (2H, m), 2.27 (2H, m).

Example 12

2-t-butoxycarbonylamino-3-(4-methoxyphenylthio)propionic acid benzylester

To a solution of 2-t-butoxycarbonylamino-3-hydroxypropionic acid benzylester (29.5 g) in dichloromethane (300 ml), triethylamine (21 ml) andmesyl chloride (8.6 ml) were added and the reaction solution was stirredfor 30 minutes at 4° C. The reaction solution was added to 1 Nhydrochloric acid cooling with ice. The obtained yellow oil wasdissolved into dichloromethane (300 ml), and diisopropylethylamine (17ml) and 4-methoxybenzenethiol (12 ml) were added thereto at 4° C. andthe reaction solution was stirred for 3 hours at room temperature andconcentrated. The residue was purified by column chromatography(n-hexane:ethyl acetate=8:1) to give the title compound (24.8 g) havingthe following physical data.

TLC: Rf 0.65 (ethyl acetate:n-hexane=1:2),

NMR (CD₃OD): δ 7.42-7.20 (7H, m), 6.80 (2H, d, J=9.0 Hz), 5.35 (1H, m),5.02 (1H, d, J=12.5 Hz), 4.85 (1H, d, J=12.5 Hz), 4.55 (1H, m), 3.78(3H, s), 3.25 (2H, d, J=5.0 Hz), 1.40 (9H, s).

Example 13

2-t-butoxycarbonylamino-3-(4-methoxyphenylsulfonyl)propionic acid benzylester

To a solution of the compound prepared in Example 12 (20.9 g) indichloromethane (200 ml), 70% m-chloroperbenzoic acid (26.0 g) was addedand the reaction solution was stirred for 72 hours at room temperature.The reaction solution was added to water and it was extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate, filterd and concentrated. The residue was washed with n-hexaneand the precipitate was dissolved into ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate, asaturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was washedwith n-hexane to give the title compound (16.7 g) having the followingphysical data.

TLC: Rf 0.29 (ethyl acetate:n-hexane=1:2),

NMR (CD₃OD) δ 7.78 (2H, d, J=9.0 Hz), 7.45-7.30 (5H, m), 6.98 (2H, d,J=9.0 Hz), 5.50 (1H, d, J=7.5 Hz), 5.18 (1H, d, J=11.0 Hz), 5.06 (1 H.d, J=11.0 Hz), 4.60 (1H, m), 3.88 (3H, s), 3.72 (2H, d, J=5.0 Hz), 1.35(9H, s).

Example 14

2-t-butoxycarbonylamino-3-(4-methoxyphenylsulfonyl)propionic acid

Under an atmosphere of nitrogen, to a solution of the compound preparedin Example 13 (1.35 g) in THF (15 ml), 10% palladium-carbon (100 g) wasadded and the reaction solution was stirred for 45 minutes at roomtemperature under an atmosphere of hydrogen. 10% palladium-carbon wasremoved from the reaction solution and then the solution wasconcentrated. The residue was washed with ether to give the titlecompound (1.02 g) having the following physical data.

TLC: Rf 0.57 (chloroform:methanol:acetic acid=9:1:1),

NMR (DMSO-d₆): δ 7.79 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz), 7.05(1H, d, J=8.4 Hz), 4.26 (1H, m), 3.87 (3H, s), 3.61 (2H, m), 1.32 (9H,s).

Example 15

2-amino-3-(4-methoxyphenylsulfonyl)propionic acid benzyl esterhydrochloride

The title compound having the following physical data was obtained bythe same procedure as Example 8, using the compound prepared in Example13.

TLC: Rf 0.54 (chloroform:methanol=18:1),

NMR (DMSO-d₆): δ 9.00-8.80 (3H, br), 7.85 (2H, d, J=9.0 Hz), 7.42-7.35(5H, m), 7.15 (2H, d, J=9.0 Hz), 5.18 (1H, d, J=12.5 Hz), 4.98 (1H, d,J=12.5 Hz), 4.45 (1H, t, J=5.0 Hz), 3.95 (2H, d, J=5.0 Hz), 3.86 (3HJ,s).

Example 16˜16(2)

The following compounds were obtained by the same procedure as Example9, using the compound prepared in Example 15 and the correspondingcarboxylic acids.

Example 16

2-[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid benzyl ester

TLC: Rf 0.51 (ethyl acetate:n-hexane=1:1),

NMR (DMSO-d₆): δ 8.88 and 8.75 (total 1H, d and d, J=7.8 and 7.8 Hz),7.79 and 7.74 (total 2H, d and d, J=9.0 and 9.0 Hz), 7.42-7.20 (10H, m),7.14 and 7.10 (total 2H, d and d, J=9.0 and 9.0 Hz), 5.20-4.95 (3H, m),4.80-4.65 and 4.63-4.45 (total 1H, m and m), 3.88 and 3.87 (total 3H, sand s), 3.80-3.60 (2H, m), 1.38 (9H, s).

Example 16(1)

2-acetylamino-3-(4-methoxyphenylsulfonyl)propionic acid benzyl ester

TLC: Rf 0.53 (chloroform:methanol=18:1),

NMR (CDCl₃): 7.76 (2H, d, J=9.2 Hz), 7.45-7.30 (5H, m), 6.99 (2H, d,J=9.2 Hz), 6.54 (1H, d, J=7.0 Hz), 5.19 (1H, d, J=11.8 Hz), 5.09 (1H, d,J=11.8 Hz), 4.87 (1H, m), 3.88 (3H, s), 3.80-3.70 (2H, m), 1.93 (3H, s).

Example 16(2)

2-[N-[N-(t-butoxycarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid benzyl ester

TLC: Rf 0.31 (ethyl acetate:n-hexane=1:1),

NMR (DMSO-d₆): δ 8.40 (1H, d, J=8.0 Hz), 7.80 (2H, d, J=9.0 Hz),7.45-7.25 (5H, m), 7.18 (2H, d, J=9.0 Hz), 6.95 (1H, m), 5.08 (2H, s),4.70 (1H, m), 3.88 (3H, s), 3.80-3.60 (2H, m), 3.45-3.30 (2H, m, overlapwith H₂O in DMSO), 1.40 (9H, s).

Example 17˜17(2)

The following compounds were obtained by the same procedure as Example14, using the compounds prepared in Example 16˜16(2).

Example 17

2-[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid

TLC: Rf 0.30 (chloroform:methanol:acetic acid 90:10:1),

NMR (CD₃OD): δ 7.81 and 7.72 (total 2H, each d, J=9.2 Hz), 7.35 (5H, m),7.10 and 7.50 (total 2H, each d, J=9.2 Hz), 5.11 and 5.03 (total 1H,each brs), 4.76 and 4.55 (total 1H, each dd, J=8.6 Hz, 3.7 Hz), 3.90 and3.89 (total 3H, each s), 3.84-3.57 (2H, m), 1.44 (9H, s).

Example 17(1)

2-acetylamino-3-(4-methoxyphenylsulfonyl)propionic acid

TLC: Rf 0.46 (ethyl acetate:acetic acid:water=3:1:1),

NMR (CDCl₃+CD₃OD): δ 7.82 (2H, d, J=8.8 Hz), 7.03(2H, d, J=8.8 Hz), 4.73(1H, m), 3.89 (3H, s), 3.82-3.70 (2H, m), 1.91 (3H, s).

Example 17(2)

2-[N-[N-(t-butoxycarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid

TLC: Rf 0.38 (chloroform:methanol:acetic acid=80:20:1),

NMR (CDCl₃+CD₃OD): δ 7.82 (2H, d, J=9.0 Hz), 7.03 (2H, d, J=9.0 Hz),4.75 (1H, m), 3.89 (3H, s), 3.75 (4H, m), 1.46 (9H, s).

Example 18˜18(2)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 8→Example 9 (the corresponding carboxylic acidsare used.)→Example 14, using the compound prepared in Example 16(2).

Example 18

2-[N-[N-(t-butoxycarbonyl)phenylglycyl-glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid

TLC: Rf 0.43 (chloroform:methanol:acetic acid 80:20:1),

NMR (DMSO-d₆): δ 8.29 (2H, m), 7.77 and 7.75 (total 2H, each d, J=9.0Hz), 7.41 (2H, m), 7.30 (4H, m), 7.12 and 7.10 (total 2H, each d, J=9.0Hz), 5.25 (1H, 2m), 4.53 (1H, m), 3.84 and 3.82 (total 3H, each s),3.78-3.45 (4H, m), 1.38 (9H, s).

Example 18(1)

2-[N-(N-acetylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionic acid

TLC: Rf 0.32 (ethyl acetate acetic acid:water=3:1:1),

NMR (DMSO-d₆+CD₃OD): δ 7.80 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz),4.60 (1H, dd, J=8.3 and 4.0 Hz), 3.89 (3H, s), 3.85-3.50 (4H, m), 1.89(3H, s).

Example 18(2)

2-[N-[N-(benzylcarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid

TLC: Rf 0.61 (ethyl acetate:acetic acid:water=3:1:1),

NMR (DMSO-d₆+CD₃OD): δ 7.79 (2H, d, J=8.8 Hz), 7.40-7.20 (5H, m), 7.12(2H, d J=8.8 Hz), 4.59 (1H, m), 3.85 (3H, s), 3.82-3.40 (6H, m).

Example 19˜19(6)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 9 Example 14, using the compounds prepared inExample 14, 17˜17(2), 18˜18(2).

Example 19

N-hydroxy-2-t-butoxycarbonylamino-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.62 (chloroform:methanol:acetic acid=9:1:1).

Example 19(1)

N-hydroxy-2-[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.55 (chloroform:methanol:acetic acid=90:10:1),

NMR (DMSO-d₆): δ 10.65 (1H, br), 9.04 and 8.98 (total 1H, each br), 8.59and 8.57 (total 1H, each d, J=8.2 Hz), 7.77 and 7.66 (total 2H, each d,J=9.0 Hz), 7.32 (6H, m), 7.13 and 7.08 (total 2H, each d, J=9.0 Hz),5.00 (1H, d, J=8.2 Hz), 4.50 (1H, m), 3.87 (3H, s), 3.59 (2H, m), 1.38(9H, s).

Example 19(2)

N-hydroxy-2-acetylamino-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.31 (chloroform:methanol:acetic acid=80:10:1),

NMR (DMSO-d₆): δ 11.00-8.60 (2H, br), 8.06 (1H, d, J=8.6 Hz), 7.76 (2H,d, J=8.0 Hz), 7.14 (2H, d, J=8.0 Hz), 4.56 (1H, m), 3.86 (3H, s), 3.55(2H, m), 1.63 (3H, s).

Example 19(3)

N-hydroxy-2-[N-[N-(t-butoxycarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.40 (chloroform:methanol:acetic acid=90:10:1),

NMR (DMSO-d₆): δ 10.62 (1H, brs), 8.99 (1H, brs), 8.15 (1H, d, J=8.4Hz), 7.75 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 6.87 (1H, m), 4.59(1H, m), 3.87 (3H, s), 3.65-3.24 (4H, m), 1.39 (9H, s).

Example 19(4)

N-hydroxy-2-[N-[N-(t-butoxycarbonyl)phenylglycyl-glycyl]amino]-3-(4-melhoxyphenylsulfonyl)propionamide

TLC: Rf 0.45 (chloroform:methanol:acetic acid=90:10:1),

NMR (DMSO-d₆): δ 11.00-10.40 (1H, br), 9.20-8.60 (1H, br), 8.23 (2H, m),7.75 and 7.73 (total 2H, each d, J=8.6 Hz), 7.44-7.29 (6H, m), 7.12 and7.08 (total 2H, each d, J=8.6 Hz), 5.24 (1H, m), 4.60 (1H, m), 3.83 and3.80 (total 3H, each s), 3.66-3.33 (4H, m, overlap with H2O in DMSO),1.38 (9H, s).

Example 19(5)

N-hydroxy-2-[N-(N-acetylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.45 (ethyl acetate:acetic acid:water=3:1:1),

NMR (DMSO-d₆+CD₃OD): δ 7.76 (2H, m), 7.14 (2H, m), 4.60 (1H, m), 3.87(3H, s), 3.70-3.30 (4H, m), 1.87 (3H, s).

Example 19(6)

N-hydroxy-2-[N-[N-(benzylcarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide

TLC: Rf 0.37 (chloroform:methanol:acetic acid=90:10:1),

NMR (DMSO-d₆+CD₃OD): δ 7.78 (2H, m), 7.30 (7H, m), 4.60 (1H, m),3.90-3.30 (9H, m).

Example 20˜20(4)

The following compounds were obtained by the same procedure as Example8, using the compounds prepared in Example 14, 19, 17, 19(1), 19(4).

Example 20

2-amino-3-(4-methoxyphenylsulfonyl)propionic acid trifluroacetic acidsalt

TLC: Rf 0.60 (chloroform:methanol:acetic acid=5:4:1),

NMR (CD₃OD): δ 7.94 (2H, d, J=9.2 Hz), 7.18 (2H, d, J=9.2 Hz), 4.43 (1H, dd, J=8.6 Hz, 3.4 Hz), 3.92 (3H, s), 3.89 (1H, dd, J=15.2 Hz, 3.4 Hz),3.71 (1H, dd, J=15.2 Hz, 8.6 Hz).

Example 20(1)

N-hydroxy-2-amino-3-(4-methoxyphenylsulfonyl)propionamide hydrochloride

TLC: Rf 0.64 (chloroform:methanol:acetic acid=5:4 1),

NMR (DMSO-d₆): δ 11.38 (1H, s), 9.60-9.25 (1H, br), 8.90-8.50 (3H, br),7.90 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 3.90 (4H, m), 3.75 (2H,m).

Example 20(2)

2-[N-(phenylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionic acidtrifluroacetic acid salt

TLC: Rf 0.24 and 0.29 (ethyl acetate:acetic acid:water=3:1:1),

NMR (CD₃OD) δ 7.83 and 7.67 (total 2H, each d, J=8.8 Hz), 7.48 (5H, m),7.13 and 7.03 (total 2H, each d, J=8.8 Hz), 4.88 and 4.61 (total 2H,each m, overlap with H₂O in CD₃OD), 3.91 and 3.89 (total 3H, each s),3.80 and 3.73 (total 1H, each m), 3.62-3.50 (1H, m).

Example 20(3)

N-hydroxy-2-[N-(phenylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamidetrifluroacetic acid salt

TLC: Rf 0.46 and 0.51 (ethyl acetate:acetic acid:water=3:1:1),

NMR (DMSO-d₆): δ 10.90 (1H, br), 9.04 (2H, m), 8.58 (3H, br), 7.82 and7.58 (total 2H, each d, J=8.8 Hz), 7.45 (5H, m), 7.17 and 7.06 (total2H, each d, J=8.8 Hz), 4.98 and 4.81 (total 1H, each br), 4.50 (1H, m),3.88 and 3.86 (total 3H, each s), 3.64 (1H, m), 3.40 (1H, m, overlapwith H₂O in DMSO).

Example 20(4)

N-hydroxy-2-[N-(phenylglycyl-glycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamidetrifluroacetic acid salt

TLC: Rf 0.48 (ethyl acetate:acetic acid:water=3:1:1),

NMR (DMSO-d₆): δ 10.81 (1H, m), 9.00 (1H, m), 8.64 (4H, m), 8.35 (1H,m), 7.77 and 7.74 (total 2H, each d, J=8.8 Hz), 7.53 (2H, m), 7.43 (3H,m), 7.15 and 7.07 (total 2H, each d, J=8.8 Hz), 5.07 (1H, m), 4.61 (1H,m), 3.87 and 3.79 (total 3H, each s), 3.68-3.34 (4H, m, overlap with H₂Oin DMSO).

Reference Example 5

S-oxiranecarboxylic acid t-butyl ester

To a solution of S-oxiranecarboxylic acid potassium salt (1.26 g) indichloromethane (45 ml), pyridinium p-tosylate (1.50 g) and N,N′-diisopropyl-O-t-butylisourea (1.50 g) were added at 0° C. and thereaction solution was stirred for 4 hours at room temperature. Thereaction solution was passed through a short silica gel column(n-hexane:ethyl acetate=3:1) to give the title compound (932 mg) havingthe following physical data.

TLC: Rf 0.70 (ethyl acetate:n-hexane=1:3),

NMR (CDCl₃): δ 3.32 (1H, dd, J=2.8 Hz, 3.7 Hz), 2.94-2.85 (2H, m), 1.50(9H, s).

Example 21

2R-hydroxy-3-(4-bromophenylsulfonyl)propionic acid t-butyl ester

To a mixture solution of the compound prepared in Reference example 5(565 mg) in water (8.0 ml)+benzene (8.0 ml), poly ethylene glycol 4000(98 mg) and 4-bromophenylsulfinic acid sodium salt (4.3 g) were addedand the reaction solution was refluxed for 7 hours. The reactionsolution was added to water and it was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (toluene:ethyl acetate=8 1) to give the title compound(490 mg) having the following physical data.

TLC: Rf 0.56 (ethyl acetate:n-hexane=1:2),

NMR (CDCl₃): δ 7.28 (2H, d, J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz), 4.55-4.48(1H, m), 3.63 (1H, dd, J=3.0, 14.7 Hz), 3.44 (1H, dd, J=7.9, 14.7 Hz),3.08 (1H, d, J=4.1 HZ), 1.51 (9H, s).

Example 22

2R-hydroxy-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid

The title compound was obtained by the same procedure as a series ofreactions of Example 7→Example 8, using the compound prepared in Example21.

TLC: Rf 0.23 (chloroform:methanol:acetic acid=8:1:1),

NMR (DMSO-d₆3): δ 7.91 (2H, d, J=8.0 Hz), 7.75 (2H, d, J=8.0 Hz), 7.50(2H, d, J=8.0 Hz), 7.27 (2H, d, J=8.0 Hz), 4.22-4.26 (1H, m), 3.46-3.64(2H, m), 2.35 (3H, s).

Example 23

2S-hydroxy-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid

The title compound was obtained by the same procedure as Referenceexample 5→Example 21→Example 7→Example 8, using the R-oxiranecarboxylicacid potassium salt instead of S-oxiranecarboxylic acid potassium saltin Reference example 5.

TLC: Rf 0.25 (chloroform:methanol:acetic acid=8:1:1),

NMR (DMSO-d₆): δ 13.21-12.23 (1H, br.), 7.92 (2H, d, J=8.5 Hz), 7.76(2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.2 Hz), 7.27 (2H, d, J=8.2 Hz),4.41-4.35 (1H, m), 3.75-3.56 (2H, m), 2.36 (3H, s).

Example 24

3-[4-(4-tolylethynyl)phenylsulfonyl] butyric acid

The title compound was obtained by the same procedure as a series ofreactions of Example 1→Example 5→Example 7→Example 8, using 2-butenoicacid t-butyl ester and 4-bromothiophenol instead of 2-propenoic acidt-butyl ester and 4-aminothiophenol, respectively, in Example 1

TLC: Rf 0.47 (chloroform:methanol:water=4:1:0.1),

NMR (DMSO-d₆) δ 7.92 (2H, d, J=8.6 Hz), 7.81 (2H, d, J=7.8 Hz), 7.52(2H, d, J=8.6 Hz), 7.29 (2H, d, J=7.8 Hz), 3.71-3.60 (1H, m), 2.76 (1H,dd, J=16.3 Hz, 4.7 Hz), 2.43-2.30 (4H, m), 1.24 (3H, d, J=7.0 Hz).

Example 25

3-[4-(4-tolylcarbonylmethyl)phenylsulfonyl]propionic acid

The title compound was obtained by the same procedure as a series ofreactions of Example 7→Example 8, using the compound prepared in Example6.

TLC: Rf 0.46 (ethyl acetate:acetic acid=99:1),

NMR (DMSO-d₆): δ 7.96 (2H, d, J=8.2 Hz), 7.84 (2H, d, J=8.2 Hz), 7.54(2H, d, J=8.2 Hz), 7.36 (2H, d, J=8.2 Hz), 4.54 (2H, s), 3.51 (2H, t,J=7.4 Hz), 2.60-2.45 (2H), 2.39 (3H,s).

Example 26

3-[4-(4-tolylvinyl)phenylsulfonyl]propionic acid

(1) intermediate:

the preparation of3-[4-[2-hydroxy-2-(4-tolyl)ethyl]phenyl]sulfonylpropionic acid

To a solution of the compound prepared in Example 25 (347 mg) in ethanol(20 ml), sodium borohydride (111 mg) was added and the reaction solutionwas stirred for 1 hour at room temperature. The reaction mixture wasconcentrated, neutralized by adding 1 N hydrochloric acid and extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate,concentrated and washed with ether to give the above intermediate (273mg) having the following physical data.

TLC: Rf 0.33 (chloroform:methanol:acetic acid=90:10:1),

NMR (CD₃OD): δ 7.76 (2H, d, J=8.4 Hz), 7.39 (2H, d, J=8.4 Hz), 7.16 (2H,d, J=8.2 Hz), 7.10 (2H, d, J=8.2 Hz), 4.94-4.78 (1H), 3.45 (2H, t, J=7.0Hz), 3.20-2.98 (2H,m), 2.61 (2H, t, J=7.0 Hz), 2.29 (3H, s).

(2) title compound:

the preparation of 3-[4-(4-tolylvinyl)phenylsulfonyl]propionic acid

To a solution of the above intermediate (273 mg) in toluene (10 ml),p-toluenesulfonic acid 1 hydrate (30 mg) was added and the reactionsolution was stirred for 2 hours at 50° C., 2 hours at 70° C., andfurther 4 hours at 90° C. The reaction mixture was filtered after thetemperature of the reaction mixture was cooled to room temperature togive the title compound (221 mg) having the following physical data.

TLC: Rf 0.25 (chloroform:methanol=85:15),

NMR (CDCl₃+CD₃OD): δ 7.87 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz),7.45 (2H, d, J=8.0 Hz), 7.25 (1H, d, J=1 6.2 Hz), 7.20 (2H, d, J=8.2Hz), 7.08 (1H, d, J=16.2 Hz), 3.44 (2H, t, J=7.2 Hz), 2.73 (2H, t, J=7.2Hz), 2.38 (3H, s).

Example 27˜27(2)

The title compound was obtained by the same procedure as a series ofreactions of Example 7→Example 8, using the compound prepared inReference example 2.

Example 27

2-methyl-3-[4-(1-heptynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.33 (chloroform:methanol=9:1),

NMR (DMSO-d₆): δ 12.53 (1H, br s), 7.82 (2H, d, J=8.4 Hz), 7.61 (2H, d,J=8.4 Hz), 3.61 (1H, dd, J=7.4 Hz, J=14.6 Hz), 3.39 (1H, dd, J=5.3 Hz,J=14.6 Hz), 2.70-2.56 (1H, m), 2.45 (2H, t, J=7.2 Hz), 1.64-1.22 (6H,m), 1.14 (3H, d, J=7.4 Hz), 0.87 (3H, t, J=6.8 Hz).

Example 27(1)

2-methyl-3-[4-(2-benzofuranyl)phenylsulfonyl]propionic acid

TLC: Rf 0.37 (chloroform methanol 4:1),

NMR (DMS-d₆): δ 12.57 (1H, br s), 8.17 (2H, d, J=8.2 Hz), 7.99 (2H, d,J=8.2 Hz), 7.74-7.65 (3H, m), 7.43-7.26 (2H, m), 3.67 (1H, dd, J=7.0 Hz,J=14.7 Hz), 3.45 (1H, dd, J=5.3 Hz, J=14.7 Hz), 2.80-2.63 (1H, m), 1.17(3H, d, J=7.0 Hz).

Example 27(2)

2-methyl-3-[4-(4-hydroxy-but-1-ynyl)phenylsulfonyl]propionic acid

TLC: Rf 0.36 (chloroform:methanol:acetic acid=9:1:0.5),

NMR (DMSO-d₆): δ 7.83 (2H, d, J=8.4 Hz), 7.62 (2H, d, J=8.4 Hz), 4.07(1H, br s), 3.66 (1H, dd, J=7.2 Hz, J=1 4.9 Hz), 3.58 (2H, t, J=6.7 Hz),3.34-3.25 (2H, m), 2.58 (2H, t, J=6.7 Hz), 1.12 (3H, d, J=7.2 Hz).

Example 28˜28(3)

The following compounds were obtained by the same procedure as a seriesof reactions of Example 9→Example 11, using the compounds prepared inExample 27˜27(2), 8(5).

Example 28

N-hydroxy-2-methyl-3-[4-(1-heptynyl)phenylsulfonyl]propionamide

TLC: Rf 0.34 (chloroform:methanol=9:1),

NMR (DMSO-d₆): δ 10.54 (1H, br s), 7.82 (2H, d, J=8.6 Hz), 760 (2H, d,J=8.6 Hz), 3.55 (1H, dd, J=7.3 Hz, J=14.3 Hz), 3.28 (1H, dd, J=5.1 Hz,J=14.3 Hz), 2.64-2.39 (3H, m), 1.63-1.21 (6H, m), 1.06 (3H, d, J=7.3Hz), 0.87 (3H, t, J=7.1 Hz).

Example 28(1)

N-hydroxy-2-methyl-3-[4-(2-benzoluranyl)phenylsulfonyl]propionamide

TLC: Rf 0.22 (chloroform:methanol=9:1),

NMR (DMSO-d₆): δ 10.57 (1H, br s), 8.80 (1H, br s), 8.16 (2H, d, J=8.6Hz), 7.98 (2H, d, J=8.6 Hz), 7.74-7.65 (3H, m), 7.43-7.26 (2H, m), 3.61(1H, dd, J=7.3 Hz, J=14.3 Hz), 3.32 (1H, dd, J=5.2 Hz, J=14.3 Hz), 2.59(1H, m), 1.09 (3H, d, J=7.3 Hz).

Example 28(2)

N-hydroxy-2-methyl-3-[4-(4-hydroxy-but-1-ynyl)phenylsuifonyl]propionamide

TLC: Rf 0.20 (chloroform:methanol acetic acid 9:1:0.5),

NMR (DMSO-d.): δ 10.54 (1H, br s), 8.79 (1H, s), 7.82 (2H, d, J=8.3 Hz),7.61 (2H, d, J=8.3 Hz), 3.66-3.48 (3H, m), 3.38-3.20 (1H, m), 2.61-2.50(3H, m), 1.05 (3H, d, J=7.0 Hz).

Example 28(3)

N-hydroxy-2-methyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionamide

TLC: Rf 0.29 (chloroform:methanol=9:1),

NMR (DMSO-d₆) δ 10.56 (1H, br s), 7.89 (2H, d, J=8.8 Hz), 7.76 (2H, d,J=8.8 Hz), 7.48 (2H, d, J=8.0 Hz), 7.25 (2H, d, J=8.0 Hz), 3.59 (1H, dd,J=7.1 Hz, J=1 4.4 Hz), 3.32 (1H, dd, J=5.0 Hz, J=4.4 Hz), 2.67-2.54 (1H,m), 2.33 (3H, s), 1.07 (3H, d, J=7.1 Hz).

Example 29

3-[4-(phenylethynyl)phenylsulfinyl]propionic acid

3-[4-(phenylethynyl)phenylsulfinyl]propionic acid t-butyl ester (t-butylester of the title compound) was obtained by the same procedure as aseries of reactions of Reference example 1→Example 4→Example 7, usingthe compound prepared in Example 1(1). The title compound having thefollowing physical data was obtained by the same procedure as Example 8,using t-butyl ester.

TLC: Rf 0.37 (chloroform:methanol water=4:1:0.1),

NMR (DMSO-d₆) δ 7.79-7.72 (4H, m), 7.63-7.58 (2H, m), 7.48-7.44 (3H, m),3.37-3.23 (1H, m), 3.07-2.93 (1H, m), 2.69-2.50 (1H, m), 2.42-2.27 (1H,m).

Example 30

3-[4-(phenylethynyl)phenylthio]propionic acid

To a solution of the t-butyl ester prepared in the course of Example 29(46 mg) in THF (2 ml), Lawesson's Reagent (55 mg) was added at 0° C. andthe reaction solution was stirred for 15 minutes at 0° C. The oilobtained by concentrating of the reaction solution, was purified bysilica gel column chromatography (chloroform:methanol=97:3) to give thetitle compound (11 mg) having the following physical data.

TLC: Rf 0.49 (chloroform:methanol:water=4:1:0.1),

NMR (CDCl₃+CD₃OD (2 drops)): δ 7.55-7.29 (9H, m), 3.20 (2H, t, J=7.4Hz), 2.65(2H, t, J=7.4 Hz).

Example 31

3-[4-(benzoylamino)phenylsulfonyl]-2-propenoic acid

The title compounds having the following physical data were obtained bythe same procedure as a series of reactions of Example 1→Example2→Example 4, followed by the separation procedure of E and Z by passingthrough a silica gel column, further followed by the same procedure asExample 8, using 2-propynoic acid t-butyl ester instead of 2-propenoicacid t-butyl ester in Example 1.

(1) sis form

TLC: Rf 0.68 (chloroform:methanol:water=6:4:0.5),

NMR (DMSO-d₆): δ 10.72 (1H, s), 8.09 (2H, d, J=8.9 Hz), 8.00 (2H, d,J=7.8 Hz), 7.90 (2H, d, J=8.9 Hz), 7.62-7.56 (3H, m), 6.93 (1H, d,J=12.7 Hz), 6.83 (1H, d, J=12.7 Hz).

(2) trans form

TLC: Rf 0.70 (chloroform:methanol:water=6:4:0.5),

NMR (DMSO-d₆): δ 10.73 (1H, s), 8.12 (2H, d, J=9.0 Hz), 8.02-7.92 (4H,m), 7.63-7.57 (3H, m), 7.66 (1H, d, J=13.8 Hz), 6.67 (1H, d, J=13.8 Hz).

Example 32

3-(4-bromophenylsulfonyl)propionic acid

The title compound having the following physical data was obtained bythe same procedure as Example 8, using the compound prepared in Example6.

TLC: Rf 0.41 (chloroform:methanol:acetic acid=100:10:1),

NMR (CDCl₃+CD₃OD (3 drops)): δ 7.79 (2H, d, J=9.0 Hz), 7.74 (2H, d,J=9.0 Hz), 3.44 (2H, m), 2.72 (2H, m).

[Formulation example]

Formulation example 1

The following components were admixed in conventional method and punchedout to obtain 100 tablets each containing 50 mg of active ingredient.

3-[4-(phenylcarbonylamino)phenylsulfonyl]propionic acid 5.0 gCarboxymethyl Cellulose calcium (disintegrating agent) 0.2 g Magnesiumstearate (lubricating agent) 0.1 g Microcrystalline cellulose 4.7 g

Formulation example 2

The following components were admixed in conventional method. Thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freeze-dried to obtain 100 ampoules each containing 20mg of the active ingredient.

3-[4-(phenylcarbonylamino)phenylsulfonyl]propionic acid 2.0 g mannitol20 g distilled water 1000 ml

What is claimed is:
 1. A method of inhibiting matrix metalloproteinaseby administering in a pharmaceutically acceptable manner aryl sulfide,aryl sulfoxide, or aryl sulfone of the formula (I)

wherein R¹ is hydrogen, or C1-4 alkyl; , R² is —COOR⁷ or —CONHOR⁸; R⁷ishydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,—OCOR²³ wherein R²³ is C1-4 alkyl, or —CONR²⁴R²⁵wherein R²⁴and R^(25,)each independently, is hydrogen or C1-4 alkyl; R⁸ is hydrogen, C1-8alkyl, phenyl, or C1-4 alkyl substituted by phenyl; E is —CONR⁹—,—NR⁹CO, —OCO—, —COO—, —CH₂—O—, —CO—CH₂—, —(CH₂)₂—, —CH═CH— or —C≡C—wherein R⁹ is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkyl substituted byphenyl; with the proviso that the left side of each of the groups isattached to the J group; J is a bond or C1-8 alkylene; A is 1) hydrogen,2) C1-8 alkyl, 3) Ar group which is a carbocyclic ring or heterocyclicring optionally substituted by 1-3 of i) C1-15 alkyl, ii) C1-15 alkoxy,iii) halogen, iv) nitro, v) cyano, vi) guanidino, vii) amidino, viii)hydroxy, ix) benzyloxy, x) NR¹²R¹³ wherein R¹² and R¹³, eachindependently, is hydrogen, C1-4 alkyl or —COOR¹⁴ wherein R¹⁴ is C1-4alkyl or benzyloxy, xi) —COOR¹⁵ wherein R¹⁵ is hydrogen, C1-4 alkyl,phenyl, or C1-4 alkyl substituted by phenyl, xii) trifluoromethyl, xiii)carbocyclic ring, xiv) heterocyclic ring or xv) C1-4 alkyl substitutedby hydroxy, C1-4 alkoxy, NR¹²R¹³, —COOR¹⁵, carbocyclic ring orheterocyclic ring, or 4) C1-4 alkyl substituted by hydroxy or C1-4alkoxy, or A, J and E taken together, represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷ orheterocyclic ring, wherein R¹⁶ and R¹⁷, each independently, is hydrogen,C1-4 alkyl, —COOR¹⁸ wherein R¹⁸ is C1-4 alkyl or benzyl, wherein when A,J and E taken together represents heterocyclic ring this heterocyclicring may be optionally substituted by 1-4 of C1-4 alkyl, C1-4 alkoxy,halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro,NR²⁴R²⁵ or CONR²⁴R²⁵; R³ and R⁴, each independently, is (1) hydrogen,(2) C1-8 alkyl wherein one of the carbon atom in C1-8 alkyl may bereplaced by a sulfur atom, (3) —COOR¹⁹ wherein R¹⁹ is hydrogen, C1-8alkyl, phenyl, or C1-4 alkyl substituted by phenyl, (4) Ar₁ group iscarbocyclic ring or heterocyclic ring optionally substituted by 1-3 ofC1-4 alkyl, C1-4 alkoxy, halogen, hydroxy or trifluoromethyl, (5)hydroxy, (6) —N²⁰R²¹ wherein R²⁰ and R²¹, each independently, ishydrogen, C1-4 alkyl, —COOR²² or —COR²² wherein R²² is C1-4 alkyl orbenzyl, (7)

wherein R^(a) is hydrogen or phenyl, R^(b) is hydrogen, —COOR²² or—COR²², p is 1 or 2, or (8) C1-8 alkyl substituted by substituentselected from the following (a)-(f) wherein one of the carbon atom inC1-8 alkyl may be replaced by a sulfur atom; (a) —COOR¹⁹, (b) C1-4alkoxy, (c) hydroxy, (d) benzyloxy, (e) —NR²⁰R²¹, or (f) Ar₁ group, orR³ and R⁴ taken together with the carbon to which they are attached,form C3-7 cycloalkyl; R⁵ and R⁶ are hydrogen or methyl, or R³ and R⁵taken together, form a bond; n is 0, 1 or 2; with the proviso that: whenA, J and E taken together, form phenyl, and R² is CONHOH, then n is 1 or2, or non-toxic salts thereof, as active ingredient.
 2. Aryl sulfide,aryl sulfoxide, or aryl sulfone derivatives of the formula (I)

wherein R¹ is hydrogen, or C1-4 alkyl; R² is —COOR⁷ or —CONHOR⁸; R⁷ ishydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl,—OCOR²³ wherein R²³ is C1-4 alkyl, or —CONR²⁴R²⁵ wherein R²⁴ and R²⁵,each independently, is hydrogen or C1-4 alkyl; R⁸ is hydrogen, C1-8alkyl, phenyl, or C1-4 alkyl substituted by phenyl; E is —CONR⁹—,—NR⁹CO, —OCO, —COO, —CH₂—O—, —CO—CH₂—, —(CH₂)₂—, —CH═CH— or —C≡C—wherein R⁹ is hydrogen, C1-4 alkyl, phenyl, or C1-4 alkyl substituted byphenyl, with the proviso that the left side of each of the groups isattached to the J group; J is a bond or C1-8 alkylene; A is 1 )hydrogen, 2) C1-8 alkyl, 3) Ar group which is carbocyclic ring orheterocyclic ring optionally substituted by 1-3 of i) C1-15 alkyl, ii)C1-15 alkoxy, iii) halogen, iv) nitro, v) cyano, vi) guanidino, vii)amidino, viii) hydroxy, ix) benzyloxy, x) NR¹²R¹³ wherein R¹² and R¹³,each independently, is hydrogen, C1-4 ayl or —COOR¹⁴ wherein R¹⁴ is C1-4alkyl or benzyloxy, xi) —COOR¹⁵ wherein R¹⁵ is hydrogen, C1-4 alkyl,phenyl, or C1-4 alkyl substituted by phenyl, xii) trifluoromethyl, xiii)carbocyclic ring, xiv) heterocyclic ring or xv) C1-4 alkyl substitutedby hydroxy, C1-4 alkoxy, NR¹²R¹³, —COOR¹⁵ carbocyclic ring orheterocyclic ring, or 4) C1-4 alkyl substituted by hydroxy or C1-4alkoxy, or A, J and E taken together, represents methyl, halogen,trifluoromethyl, nitro, cyano, formyl, phenyl, hydroxy, NR¹⁶R¹⁷, orheterocyclic ring, wherein R¹⁶ and R¹⁷, each independently, is hydrogen,C1-4 alkyl or —COOR¹⁸ wherein R¹⁸ is C1-4 alkyl or benzyl, wherein whenA, J and E taken together are heterocyclic ring this heterocyclic ringmay be optionally substituted by 1-4 of C1-4 alkyl, C1-4 alkoxy,halogen, trifluoromethyl, hydroxy, carboxyl, C1-8 alkoxycarbonyl, nitro,NR²⁴R²⁵ or CONR²⁴R²⁵; R³ and R⁴, each independently, is (1) hydrogen,(2) C1-8 alkyl with the proviso that one of the carbon atoms in C1-8alkyl may be replaced by a sulfur atom, (3) —COOR¹⁹ wherein R¹⁹ ishydrogen, C1-8 alkyl, phenyl, or C1-4 alkyl substituted by phenyl, (4)Ar, group is carbocyclic ring or heterocyclic ring optionallysubstituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, hydroxy ortrifluoromethyl, (5) hydroxy, (6) —NR²⁰R²¹ wherein R²⁰ and R²¹, eachindependently, is hydrogen, C1-4 alkyl, —COOR²² or —COR²² wherein R²² isC1-4 alkyl or benzyl, (7)

wherein R^(a) is hydrogen or phenyl, R^(b) is hydrogen, —COOR²² or—COR²², p is 1 or 2, or (8) C1-8 alkyl substituted by substituentselected from the following (a)˜(f), wherein one of the carbon atoms inC1-8 alkyl may be replaced by a sulfur atom, (a) —COOR¹⁹ (b) C1-4alkoxy, (c) hydroxy, (d) benzyloxy, (e) —NR²⁰R²¹, or (f) Ar₁ group, orR³ and R⁴ taken together with the carbon to which they are attached,form C3-7 cycloalkyl; R⁵ and R⁶ is hydrogen or methyl, or R³ and R⁵taken together, form a bond; n is 0, 1 or 2; with the provisos that: (a)when A, J and E taken together, form phenyl, and R² is CONHOH, then n is1 or 2, (b) when R² is —COOR⁷, R⁷ is hydrogen, C1-8 alkyl, phenyl orC1-4 alkyl substituted by phenyl, then A, J and E taken together, do notrepresent methyl, halogen, trifluoromethyl, nitro, cyano, hydroxy,NR¹⁶R¹⁷ wherein R¹⁶ and R¹⁷, each independently, is hydrogen, (c) whenR² is —COOR⁷, R⁷ is hydrogen, C1-8 alkyl, phenyl or C1-4 alkylsubstituted by phenyl, A is hydrogen or C1-8 alkyl, J is a bond or C1-8alkyl, then E does not represent —CH₂—O—or —(CH₂)₂—, (d) the following(l)-(16) compounds are excluded: (1)3-(4-acetylaminophenylsulfonyl)propionic acid methyl ester, (2)3-(4-acetylaminophenylsulfonyl)propionic acid ethyl ester, (3)3-(4-vinylphenylsulfonyl)propionic acid sodium salt, (4)3-(4-carboxyphenylsulfonyl)propionic acid, (5)3-(4-formylphenylsulfonyl)propionic acid ethyl ester, (6)3-(4biphenylsulfonyl)propionic acid methyl ester, (7)4-(2-carboxy-2-methylpropylmercapto)phenyl 2-phenylbutylate, (8)4-(2-carboxy-2-methylpropylsulfinyl)phenyl 2-phenylbutylate, (9)4-(2-carboxy-2-methylpropylsulfonyl)phenyl 2-phenylbutylate, (10)4-(2-carboxy-2-methylpropylmercapto)phenyl2-(4-methoxyphenyl)isobutylate, (11)4-(2-carboxy-2methylpropylmercapto)phenyl2-(3,4-diethylphenyl)isobutylate, (12)4-(2-carboxy-2-methylpropylmercapto)phenyl2-(1,2,3,4-tetrahydro-6-naphthyl)butyrate, (13)4-(2-carboxy-2-methylpropylmercapto)phenyl2-(1-methyl-2-pyrrole)butyrate, (14)4-(2-carboxy-2-methylpropylsulfinyl)phenyl2-(1-methyl-2-pyrrole)butyrate, (15)N-t-butoxy-3-(4-bromophenylthio)propionamide, (16)N-t-butoxy-3-(4biphenylthio)propionamide), or non-toxic salts thereof.3. A compound according to claim 2, in which R² is —COOR⁷.
 4. A compoundaccording to claim 2, in which R² is —CONHOR⁸.
 5. A compound accordingto claim 3 or claim 4, in which A is hydrogen, C1-8 alkyl, C1-4 alkylsubstituted by hydroxy, or A, J and E taken together, represents methyl,halogen, trifluoromethyl, nitro, cyano, formyl, hydroxy, NR¹⁶R¹⁷.
 6. Acompound according to claim 3 or claim 4, in which A is carbocyclic ringoptionally substituted by substituents, or A, J and E taken together,represents phenyl.
 7. A compound according to claim 3 or claim 4, inwhich A is heterocyclic ring optionally substituted by substituents, orA, J and E taken together, represents heterocyclic ring.
 8. A compoundaccording to claim 5, which is (1)(1)2-benzyl-3-(4-bromophenylthio)propionic acid t-butyl ester, (2)2-benzyl-3-(4-bromophenylsulfonyl)propionic acid t-butyl ester, (3)3-[4-(1-heptynyl)phenylsulfonyl]propionic acid t-butyl ester, (4)3-[4-(1-heptynyl)phenylsulfonyl]propionic acid, (5)N-t-butoxy-3-(4methoxyphenylthio)propionamide, (6)N-benzyloxy-3-(4-methoxyphenylthio)propionamide, (7)N-benzyloxy-3-(4-methoxyphenylsulfonyl)propionamide, (8)N-hydroxy-3-(4-methoxyphenylthio)propionamide, (9)N-hydroxy-3-(4-methoxyphenylsulfinyl)propionamide, (10)N-hydroxy-3-(4-methoxyphenylsulfonyl)propionamide, (11)2-t-butoxycarbonylamino-3-(4methoxyphenylthio)propionic acid benzylester, (12) 2-t butoxycarbonylamino-(4methoxyphenylsulfonyl)propionicacid benzyl ester, (13)2-t-butoxycarbonylamino-3-(4-methoxyphenylsulfonyl)propionic acid, (14)2-amino-3(4methoxyphenylsulfonyl)propionic acid benzyl esterhydrochloride, (15)2[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid benzyl ester, (16)2-acetylamino-3-(4-methoxyphenylsulfonyl)propionic acid benzyl ester,(17)(2-[N-[N-(t-butoxycarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid benzyl ester, (18)2-[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid, (19) 2-acetylamino-3-(4-methoxyphenylsulfonyl)propionic acid, (20)2-[N-[N-(t-butoxycarbonyl)glycyl[amino]-3-(4-methoxyphenylsulfonyl)propionicacid, (21)2-[N-[N-(t-butoxycarbonyl)phenylglycyl-glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid, (22)2-[N-(N-acetylglycyl)amino]-3-4-methoxyphenylsulfonyl)propionic acid,(23)2-[N-[N-(benzylcarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionicacid, (24)N-hydroxy-2-t-butoxycarbonylamino-3-(4-methoxyphenylsulfonyl)propionamide,(25)N-hydroxy-2-[N-[N-(t-butoxycarbonyl)phenylglycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide,(26) N-hydroxy-2-acetylamino-3-(4-methoxyphenylsulfonyl)propionamide,(28)N-hydroxy-2-[N-[N-(t-butoxycarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide,(28)N-hydroxy-2-[N-N-(t-butoxycarbonyl)phenylglycyl-glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide,(29)N-hydroxy-2-[N-(N-acetylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamide,(30)N-hydroxy-2-[N-[N-(benzylcarbonyl)glycyl]amino]-3-(4-methoxyphenylsulfonyl)propionamide,(31) 2-amino-3-(4-methoxyphenylsulfonyl)propionic acid trifluoroaceticacid salt, (32)N-hydroxy-2-amino-3-(4-methoxyphenylsulfonyl)propionamide hydrochloride,(33) 2-[N(phenylglycyl)amino]-3-4methoxyphenylsulfonyl)propionic acidtrifluoroacetic acid salt, (34)N-hydroxy-2-[N-(phenylglycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamidetrifluoroacetic acid salt, or (35)N-hydroxy-2-[N-(phenylglycyl-glycyl)amino]-3-(4-methoxyphenylsulfonyl)propionamidetrifluoroacetic acid salt.
 9. A compound according to claim 6, which is(1) 7(3) 3-[4-(2-pyridylethynyl)phenylsulfonyl]propionic acid t-butylester, (2) 3-[4-(2-pyridylethynyl)phenylsulfonyl]propionic acid, (3)2-methyl-3-[4-(2-benzofuranyl)phenylsulfonyl]propionic acid, or (4)N-hydroxy-2-methyl-3-[4-(2-benzofuranyl)phenylsulfonyl]propionamide. 10.A compound according to claim 7, which is (1)3-[4-(benzoylamino)phenylthio]propionic acid t-butyl ester, (2)3-(4-benzyloxyphenylthio)propionic acid 1-butyl ester, (3)3-[4-(benzoylamino)phenylsulfinyl]propionic acid t-butyl ester, (4)3-[4-(benzoylamino)phenylsulfonyl]propionic acid t-butyl ester, (5)3-[4-(benzyloxy)phenylsulfonyl]propionic acid t-butyl ester, (6)2-methyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid t-butylester, (7) 3-[4-(phenylethynyl)phenylsulfonyl]propionic acid t-butylester, (8) 3-[4-(4- methoxyphenylethynyl)phenylsulfonyl]propionic acidt-butyl ester, (9) 3-[4-(4-tolylethynyl)phenylsulionyl]propionic acidt-butyl ester, (10) 3-[4-(benzoylamino)phenylthio]propionic acid, (11)3-[4-(benzoylamino)phenylsulfinyl]propionic acid, (12)3-[4-(benzoylamino)phenylsulfonyl]propionic acid, (13)3-[4-(benzyloxy)phenylsulfonyl]propionic acid, (14)2-methyl-3-[4-(4-tolylcarbonyl methyl)phenylsulfonyl]propionic acid,(15) 2-methyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid, (16)3-[4-(phenylethynyl)phenylsulfonyl]propionic acid, (17)3-[4-(4-methoxyphenylethynyl)phenylsulfonyl]propionic acid, (18)2-benzyl-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid, (19)2R-hydroxy-3-(4-bromophenylsulfonyl)propionic acid t-butyl ester, (20)2R-hydroxy-3-[4-(4-tolylethynyl)phenyisulfonyl]propionic acid, (21)2S-hydroxy-3-[4-(4-tolylethynyl)phenylsulfonyl]propionic acid, (22)3-[4-(4-tolylethynyl)phenylsulfonyl]butyric acid, (23)3-[4-(4-tolylcarbonylmethyl)phenylsulfonyl]propionic acid, (24)3-[4-(4-tolylvinyl)phenylsulfonyl]propionic acid, (25)2-methyl-3-[4-(1-heptynyl)phenylsulfonyl]propionic acid, (26)2-methyl-3-[4-(4-hydroxy-but-1-ynyl)phenyIsulfonyl]propionic acid, (27)N-hydroxy-2-methyl-3-[4-(1-heptynyl)phenylsulfonyl]propionamide, (28)N-hydroxy-2-methyl-3-[4-(4-hydroxy-but-1-ynyl)phenylsulfonyl]propionamide,(29)N-hydroxy-2-methyl-3-[4-(4-tolylethynyl)phenylsuffonyl]propionamide,(30) 3-[4-(phenylethynyl)phenylsulfinyl]propionic acid, (31)3-[4-(phenylethynyl)phenylthio]propionic acid, (32)cis-3-[4-(benzoylamino)phenylsulfonyl]-2-propenoic acid, or (33)trans-3-[4-(benzoylamino)phenylsulfonyl]-2-propenoic acid.